Open Access

Possible stimulation of anti-tumor immunity using repeated cold stress: a hypothesis

Infectious Agents and Cancer20072:20

https://doi.org/10.1186/1750-9378-2-20

Received: 26 June 2007

Accepted: 13 November 2007

Published: 13 November 2007

Abstract

Background

The phenomenon of hormesis, whereby small amounts of seemingly harmful or stressful agents can be beneficial for the health and lifespan of laboratory animals has been reported in literature. In particular, there is accumulating evidence that daily brief cold stress can increase both numbers and activity of peripheral cytotoxic T lymphocytes and natural killer cells, the major effectors of adaptive and innate tumor immunity, respectively. This type of regimen (for 8 days) has been shown to improve survival of mice infected with intracellular parasite Toxoplasma gondii, which would also be consistent with enhanced cell-mediated immunity.

Presentation of the hypothesis

This paper hypothesizes that brief cold-water stress repeated daily over many months could enhance anti-tumor immunity and improve survival rate of a non-lymphoid cancer. The possible mechanism of the non-specific stimulation of cellular immunity by repeated cold stress appears to involve transient activation of the sympathetic nervous system, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as described in more detail in the text. Daily moderate cold hydrotherapy is known to reduce pain and does not appear to have noticeable adverse effects on normal test subjects, although some studies have shown that it can cause transient arrhythmias in patients with heart problems and can also inhibit humoral immunity. Sudden immersion in ice-cold water can cause transient pulmonary edema and increase permeability of the blood-brain barrier, thereby increasing mortality of neurovirulent infections.

Testing the hypothesis

The proposed procedure is an adapted cold swim (5–7 minutes at 20 degrees Celsius, includes gradual adaptation) to be tested on a mouse tumor model. Mortality, tumor size, and measurements of cellular immunity (numbers and activity of peripheral CD8+ T lymphocytes and natural killer cells) of the cold-exposed group would be compared to those of control groups (warm swim and no treatment). Cold-water stress would be administered twice a day for the duration of several months.

Implications of the hypothesis

If the hypothesis is supported by empirical studies and the method is shown to be safe, this could lead to the development of an adjunctive immunotherapy for some (non-lymphoid) cancers, including those caused by viral infections.

Background

Numerous studies show that small amounts of harmful or stressful agents (e.g. heat stress, cold stress, hypergravity) can be beneficial for the health of laboratory animals, the phenomenon that became known as hormesis, although evidence for possible benefits in humans is lacking at present [1, 2]. This paper presents theoretical evidence for immunomodulating properties of brief cold stress, as increasing evidence indicates that cold stress repeated daily can have a stimulating effect on cell-mediated immunity [36], while inhibiting humoral immunity to some extent [7, 8]. There is a number of ways to administer cold stress and this may account for the different effects on the immune system reported by various studies [911]. The focus of this paper is brief whole-body exposure to cold water since it has been shown to increase both activity and numbers of peripheral natural killer (NK) cells and CD8+ T lymphocytes [3, 6, 1214]. This effect could be explained by transient activation of the sympathetic nervous system (SNS) [15, 16], the hypothalamic-pituitary-adrenal (HPA) axis [17, 18] as well as the hypothalamic-pituitary-thyroid (HPT) axis [19, 20] resulting in a brief action of norepinephrine, adrenocorticotropic hormone (ACTH), beta-endorphin, and thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) on cytotoxic T lymphocytes (CTLs) and NK cells. As explained below, all of these neuroendocrine factors have been previously shown to promote expansion and/or cytolytic activity of CTLs and NK cells. Interestingly, brief cold swim stress repeated for 8 days was also reported to increase survival of mice infected with intracellular parasite Toxoplasma gondii [5], the situation that is consistent with enhancement of cellular immunity. Based on this evidence and given the fact that NK cells and CTLs are major components of an anti-tumor immune response [21], it seems logical to propose the following hypothesis.

Presentation of the hypothesis

The hypothesis is that brief cold-water stress repeated daily over many months could enhance anti-tumor immunity and improve cancer survival rate in a mouse (non-lymphoid) tumor model. While substantial efforts in the field of tumor immunology are devoted to finding ways to elicit a tumor-specific CTL response using tumor-derived antigens [22], this paper discusses a somewhat different approach of non-specific promotion of cell-mediated immune responses by increasing the total number and enhancing cytolytic potential of peripheral CTLs and NK cells. As a tide that lifts all boats, this approach could enhance endogenous (but possibly inadequate) CTL anti-tumor responses and thereby inhibit the development and growth of a tumor. Lymphocyte activation may also lead to autoimmunity, which does not appear to be the case for immunological changes associated with repeated cold stress [3, 6, 12, 23, 24]. A similar "broad activation" principle serves as a rationale for systemic interleukin-2 (IL-2) administration, which is currently used as anti-cancer immunotherapy in renal cell cancer and metastatic melanoma [25]. However, this approach proved to be rather inefficient, probably due to induction of T cell apoptosis and/or inability of the effector CD8+ T lymphocytes to infiltrate/home to the tumor site [25, 26]. On the other hand, it has been demonstrated in several mouse tumor models that tumor-specific T cells are fully mature/activated and effectively infiltrate tumors but are not able to kill the cognate tumor cells ex vivo due to defective granule exocytosis-mediated cytotoxicity [27, 28]. This defect is reversible as tumor-specific T cells that are isolated/purified from the tumor can regain lytic activity after brief in vitro culture [28]. The paper presented here hypothesizes that repeated cold stress could induce/enhance lytic activity of CD8+ T cells at the tumor site, and may also enhance innate anti-tumor immunity through expansion and activation of NK cells, all of which could result in more efficient tumor elimination. The detailed supporting evidence for this hypothesis is as follows.

General neuro-endocrine effects of brief cold stress

From available literature, one can distinguish immediate (or transient) effects of cold stress, lasting 1 to 2 hours, and longer-term (or sustained) effects of repeated (e.g. once daily) cold stress, lasting days and possibly weeks. The immediate/transient effects reported in mice and humans include: brief activation of the SNS [15, 16], of the HPA axis [17, 18] and of the HPT axis [19, 20] with a significant increase in the metabolic rate [29] and in plasma levels of norepinephrine [15, 16], ACTH [30, 31], corticosterone [7], beta-endorphin [18, 32], T3 [19, 20], T4 [20], as well as a modest or undetectable increase in the plasma levels of interleukin-6 (IL-6) [12, 13] and cortisol [33, 34] (Table 1). The sustained/longer-term effects of cold stress repeated daily or almost daily (over the period of 5 days to 6 weeks) appear to include increased plasma levels of tumor necrosis factor-α (TNF-α) [12], IL-2 [3], IL-6 [12], ACTH [35], corticosterone [3], as well as a decreased plasma level of α1-antitrypsin [12] and testosterone [6] (Table 1).
Table 1

Known effects of cold stress. "Immediate/transient" means effects of a single brief exposure to cold that last less than 1–2 hours. "Sustained/longer-term" means effects (of repeated daily or several times per week cold-water stress) that can last one day or longer.

Immediate/transient effects

Sustained/longer-term effects

Activation of:

sympathetic nervous system [15,16]

hypothalamic-pituitary-adrenal axis [17,18]

hypothalamic-pituitary-thyroid axis [19,20]

Increased resting metabolic rate [29]

An increase in plasma levels of:

adrenocorticotropic hormone [35]

corticosterone* [3]

interleukin-2 (modest/undetectable) [3,84]

interleukin-6 [12]

tumor necrosis factor-α [12]

haptoglobin [12]

hemopexin [12]

An increase in plasma levels of:

adrenocorticotropic hormone [30,31]

norepinephrine [15,16]

beta-endorphin [18,32]

corticosterone* [7]

cortisol (modest/undetectable) [33,34,82,83]

thyroid stimulating hormone [20]

triiodothyronine [19,20]

thyroxine [20]

interleukin-6 [6,13]

Decreased plasma level of interleukin-2 [84,85]

Decreased plasma levels of:

α1-antitrypsin [12]

testosterone [6]

* It is expected to have a negligible immunosuppressive effect [86,87].

Effects on maturation and peripheral recruitment of CTLs

Brief cold stress such as a cold swim has been reported to increase the level of peripheral T lymphocytes both in a transient manner after a single treatment (CD8+ T lymphocytes [11]) and in a sustained manner, when treatments are repeated daily or thrice per week (both CD4+ and CD8+ lymphocytes [3, 12]). This could be mediated by the transient action of norepinephrine on β2-adrenergic receptors of CD8+ T lymphocytes [3638] as a result of the activation of the SNS [3941], which innervates both primary and secondary lymphoid organs and can stimulate lymphocyte proliferation, maturation, and peripheral recruitment via norepinephrine release in a non-synaptic fashion (reviewed in [42]). Additionally, the cold stress-induced expansion of CTLs could be mediated by changes in other neuroendocrine factors that are known to be caused by cold stress (Table 2).
Table 2

Possible mechanisms underlying the stimulatory effects of repeated cold stress on cell-mediated immunity

 

CTLs and other cytotoxic immune cells

NK cells*

Expansion/peripheral recruitment

brief action** of the SNS [39-41] (via norepinephrine) on β2-adrenergic receptors of CD8+ T lymphocytes [36-38]; elevated plasma levels of ACTH [88,89], T4 [90], and beta-endorphin [91];

brief action** of the SNS (via norepinephrine) on β2-adrenergic receptors of NK cells [37,42,44]; upregulation of beta-endorphin [92], IL-2 [93], T3 [94] and T4 [95];

Activation

brief action** of the SNS (via norepinephrine) [36,39,96-98], beta-endorphin [91,99-101], T3 [102], or T4 [90,103,104] or sustained action of ACTH [88]; increased phagocytic index [43], downregulation of testosterone [105-107] or α1-antitrypsin [108];

-

Cytolytic activity

upregulation of ACTH [88,89], beta-endorphin [109,110], IL-2 [111-113], IL-6 [114,115], TNF-α [116-118], combination of IL-2 + IL-6 [119,120], or IL-2 + TNF-α [121]; downregulation of α1-antitrypsin [122,123];

elevated plasma levels of IL-2 [93], beta-endorphin [124-126], ACTH [127,128], T3 [129,130] or T4 [131,132];

* Continuous hypothermia [133] (lowered core body temperature which cannot normally result from a brief exposure to cold in most mammals [52,53]) or continuous exposure to acute cold (4 hours or longer [134]) have been shown to reduce both the number and activity of peripheral NK cells.

** Continuous elevated levels of norepinephrine or other β2-adrenergic agonists (3 hours or longer) appear to have an opposite effect: reduction in peripheral CTLs and NK cells and inhibition of their activity [42,135,136].

Effects on activity of CTLs

Studies show that both single and repeated (daily) brief exposure to cold can enhance antigen-induced proliferative responses of T lymphocytes and the level of activated peripheral T lymphocytes in mammals [3, 4, 6, 12, 14]. This stimulatory effect could be mediated by the brief action of the SNS (via norepinephrine), of beta-endorphin, T3, or T4 or sustained action of ACTH and IL-2 (Table 2). There is also evidence of an increased phagocytic index following brief cold stress [43], suggesting that antigen (cross-)presentation may be enhanced. Unfortunately, it is not known if cold stress can enhance cytolytic activity of peripheral cytotoxic T lymphocytes, but there is indirect evidence that this may be the case (Table 2 and [5, 24]).

Effects on maturation and peripheral recruitment of NK cells

Single brief exposure to cold appears to transiently increase the level of peripheral NK cells [11, 13]. This could be due to the increased peripheral recruitment and/or expansion of these cells, which are known to be mediated by the action of the SNS (via norepinephrine) on β2-adrenergic receptors of NK cells [37, 42, 44]. This effect could also be mediated by elevated levels of beta-endorphin, IL-2, T3 and T4 (Table 2).

Effects on activity of NK cells

Both single and repeated (daily) brief cold stress has been shown to enhance cytolytic activity of NK cells [3, 13]. This could be the result of elevated plasma levels of IL-2, beta-endorphin, ACTH, T3 or T4 (Table 2).

Other effects

Daily moderate cold water stress does not appear to have noticeable adverse effects on normal test subjects either short-term or long-term [12, 15, 24, 45] and, interestingly, in a near-life-time experiment on healthy rats, where the animals had to stand in 23°C water 4 hours per day 5 days per week, the repeated cold stress extended the lifespan by statistically insignificant 5% and somewhat reduced spontaneous incidence of tumors, especially sarcomas [24]. Based on the evidence presented earlier, more frequent exposure to cold of shorter duration, for example 5-minute cold swim stress twice per day (>7 hours apart), could have a more significant immunostimulatory effect and a less pronounced effect on metabolism compared to the above experiment. Cold water stress is also known to have an analgesic effect [32, 46, 47], which is often relevant in cancer.

Possible adverse effects

1) Water colder than 14°C can cause cutaneous pain [48, 49] and therefore would be best avoided.

2) Exposure to acute cold for extended periods of time can cause a significant drop of core body temperature (hypothermia) which can be associated with such adverse effects on health as ataxia, hypovolemia, atrial dysrhythmias, cold diuresis, and mental confusion [50, 51]. Immersion in moderately cold water in the range of 16–23°C does not appear to cause hypothermia (core temperature of 35°C or lower) in healthy human subjects, even when it lasts for several hours [52]. During this procedure, core body temperature stays virtually unchanged during the first hour [52] due to unusual efficiency of the human thermoregulatory system [53]. It should be noted that the elderly or people with certain metabolic disorders may develop hypothermia under these conditions, and thus body temperature should be monitored in these groups of people if they use cold hydrotherapy [50, 51].

3) Coldest months of the year have been shown to be associated with a higher incidence of acute heart failure and stroke [5456]. In the landmark experiment by Holloszy and Smith described above, where rats were standing in cold water 4 hours per day, the prevalence of cardiovascular problems was increased according to postmortem examination, although the average lifespan was increased insignificantly and the prevalence of malignancies declined [24]. It is not known if daily brief exposure to moderately cold water (20°C, under 15 minutes) with gradual adaptation will have similar cardiovascular effects in the long run. Studies also show that immersion in cold water can cause transient arrhythmias in some patients with heart problems [5759], although short-term cardiovascular effects of cold water immersion seem to be benign in normal test subjects [15].

4) Upper respiratory tract infections such as the flu and common cold occur predominantly although not exclusively during the cold time of the year, i.e. late fall/winter [60]. It is not known if this is due to exposure to cold, dietary patterns, or some other factors [61]. Near-life-time exposure of rats to cold water (23°C) for several hours per day was not reported to increase incidence of respiratory infections [24], as was the case for 1-hour cold water immersions (14°C) repeated 3 times per week for 6 weeks in humans [12, 15]. On the other hand, some studies show that inhalation of cold air can inhibit cell-mediated immunity in the mucosa of the respiratory tract and thus possibly increase susceptibility to respiratory viral infections [62].

5) Swimming in ice-cold water can cause transient pulmonary edema in humans [6365], which may be due to severe hypothermia among other things [51].

6) Some studies show that sudden immersion in ice-cold water can increase permeability of the blood-brain barrier in mice [66, 67], and when repeated daily can also increase mortality of neurovirulent infections (e.g. West Nile virus, Sindbis virus) due to propagation of the infection to the brain of the mice [68, 69]. Increased permeability of the blood-brain barrier can be due to the distress associated with a dive into ice-cold water because a different treatment which also causes distress to the animals, namely, isolation, has very similar adverse effects [67]. In addition, immersion in ice-cold water can rapidly cause severe hypothermia in mice [70] and hypothermia is known to increase permeability of the blood brain barrier in healthy animals [71]. The proposed adapted cold swim procedure at 20°C is not expected to compromise the blood-brain barrier in mice because it is designed to be minimally stressful (contains a gradual adaptation phase) and is brief, such that the core body temperature of the animals would remain above 35°C. The methods described in the "Testing the hypothesis" section could verify this assumption.

In summary, the review of literature suggests that winter swimming (in other words, sudden immersion in ice-cold water) may pose serious risks to health and it is possible that exposure to cold can be safer if it is brief and does not involve psychological distress, inhalation of cold air, and hypothermia. Further studies would be needed to assess the safety of the relatively non-stressful regimen of cold hydrotherapy that is proposed in this paper. At the same time, minimally stressful exposure to moderate cold still seems to have significant physiological and immunological effects [6, 13, 33, 34], which may be useful for enhancing anti-tumor immunity according to our hypothesis.

Testing the hypothesis

The hypothesis can be tested using a treatment that consists of an adapted cold swim procedure which begins with a slow and gradual lowering of a cage with laboratory animals into stirred cold water (20°C) over the period of 4–5 minutes followed by a 1- or 2-minute cold swim. The adaptation phase is expected to minimize stress and discomfort for the animals. The cage would be lifted out of the water to discontinue cold exposure and placed on proper bedding (certain cooling may still occur due to subsequent evaporation of water from the fur of the animals). The procedure is estimated to cause the core body temperature of mice to decline by approximately 2°C based on data from Wan R. et al. [70], and may have to be tested and optimized in order to avoid inducing significant hypothermia in the animals. Manual handling of individual mice would be best avoided. Cold water stress would be administered twice per day (more than 7 hours apart) according to a schedule described below. A syngeneic orthotopic mouse tumor model can be tested, for example, intradermal injection of MEB4 melanoma cell line (4 × 104 cells) in C57BL/6 mice [72] or subcutaneous injection of 6-1 tumor cell line (2 × 105 cells) in C3H/HeN mice [73]. Sixty mice can be used for a single experiment and all of them would be injected with tumor cells. One third of the animals will be assigned to the cold swim group. The other mice will be divided into two control groups: a warm swim group (Control I) and the no treatment group (Control II). Control I group will undergo adapted warm swim procedures (water temperature is 37°C) simultaneously with the cold swim (experimental) group. Control II group will undergo handling of the cage (and, possibly, manual handling of animals) similar to the experimental and Control I groups, but without immersion in water. Cold water stress would be initiated 2 weeks prior to injection of tumor cells and would be stopped for 3 days immediately after the inoculation in order to allow the skin wounds to close. Then cold water treatments would be resumed and continued for 2 months. On weekends, only one swim or, alternatively, no swims at all would be performed. At approximately 60 days postinjection, mortality, tumor incidence, and tumor size would be assessed in all three groups [72]. In addition, the numbers and cytolytic activity of peripheral NK cells [7476] as well as average numbers of CD25-positive (activated) and total peripheral CD4+ T lymphocytes and CD8+ T lymphocytes [77, 78] and their effector properties (i.e., TCR-induced cytokine production [79] and lytic function [28]) would be measured before initiation of cold water treatment (in 5–10 mice) and 60 days after the tumor inoculation in the experimental and control groups of mice. In a separate group of 10–20 tumor-injected mice, lytic activity of freshly isolated CD8+ tumor infiltrating (and peripheral) T lymphocytes would be assessed as a function of time after the initiation of cold stress treatment [28, 73].

To verify if the proposed cold stress procedure does not significantly increase permeability of the blood-brain barrier in the animals, an Evans blue extravasation assay [80, 81] can be performed in an additional small group of mice with a no-treatment control.

If the adapted cold swim is shown to be beneficial and safe in mouse tumor models, a similar regimen can be tested on human subjects, namely, adapted cold showers, 20°C, 2–5 minutes, preceded by a 5-minute gradual adaptation phase (expansion of the area of contact with water from the feet up), performed twice per day (morning and afternoon). The shower format is preferable in humans because the setup appears to take less time and effort compared to cold baths.

Implications of the hypothesis

If the theory is confirmed by empirical studies and the proposed approach is shown to be safe, then some form of cold hydrotherapy could potentially become a treatment option for some (non-lymphoid) cancers as an adjunctive immunotherapy.

Declarations

Acknowledgements

The authors thank Stephan Ladisch, M.D., whose critical comments about the method prompted them to come up with the concept of gradual adaptation. Funding was in part derived from the Children's National Medical Center/GWU Fellowship (to NAS).

Authors’ Affiliations

(1)
Department of Radiation Oncology, Virginia Commonwealth University
(2)
Center for Cancer and Immunology Research, Children's Research Institute

References

  1. Arumugam TV, Gleichmann M, Tang SC, Mattson MP: Hormesis/preconditioning mechanisms, the nervous system and aging. Ageing Res Rev. 2006, 5 (2): 165-178. 10.1016/j.arr.2006.03.003.PubMedGoogle Scholar
  2. Leslie M: How can we use moderate stresses to fortify humans and slow aging?. Sci Aging Knowledge Environ. 2005, 2005 (26): nf49-10.1126/sageke.2005.26.nf49.PubMedGoogle Scholar
  3. Shu J, Stevenson JR, Zhou X: Modulation of cellular immune responses by cold water swim stress in the rat. Dev Comp Immunol. 1993, 17 (4): 357-371. 10.1016/0145-305X(93)90007-D.PubMedGoogle Scholar
  4. Kalenova LF, Sukhovei YG, Fisher TA: Specific and nonspecific reactions of mouse immune system under the effect of short-term exposure in warm and/or cold water. Bull Exp Biol Med. 2005, 140 (6): 720-722. 10.1007/s10517-006-0065-8.PubMedGoogle Scholar
  5. Banerjee SK, Aviles H, Fox MT, Monroy FP: Cold stress-induced modulation of cell immunity during acute Toxoplasma gondii infection in mice. J Parasitol. 1999, 85 (3): 442-447. 10.2307/3285776.PubMedGoogle Scholar
  6. Jain S, Bruot BC, Stevenson JR: Cold swim stress leads to enhanced splenocyte responsiveness to concanavalin A, decreased serum testosterone, and increased serum corticosterone, glucose, and protein. Life Sci. 1996, 59 (3): 209-218. 10.1016/0024-3205(96)00286-X.PubMedGoogle Scholar
  7. Luo YM, Cheng XJ, Yuan WX: Effects of ginseng root saponins and ginsenoside Rb1 on immunity in cold water swim stress mice and rats. Zhongguo Yao Li Xue Bao. 1993, 14 (5): 401-404.PubMedGoogle Scholar
  8. Garbulinski T, Obminska-Domoradzka B, Switala M, Debowy J: Responses of neutrophils and lymphocytes in the cold stress: effects of nonsteroid anti-inflammatory drugs. Pol J Pharmacol Pharm. 1991, 43 (5): 353-359.PubMedGoogle Scholar
  9. Cheng GJ, Morrow-Tesch JL, Beller DI, Levy EM, Black PH: Immunosuppression in mice induced by cold water stress. Brain Behav Immun. 1990, 4 (4): 278-291. 10.1016/0889-1591(90)90032-L.PubMedGoogle Scholar
  10. Giberson PK, Kim CK, Hutchison S, Yu W, Junker A, Weinberg J: The effect of cold stress on lymphocyte proliferation in fetal ethanol-exposed rats. Alcohol Clin Exp Res. 1997, 21 (8): 1440-1447.PubMedGoogle Scholar
  11. Willemsen G, Carroll D, Ring C, Drayson M: Cellular and mucosal immune reactions to mental and cold stress: associations with gender and cardiovascular reactivity. Psychophysiology. 2002, 39 (2): 222-228. 10.1017/S0048577202001476.PubMedGoogle Scholar
  12. Jansky L, Pospisilova D, Honzova S, Ulicny B, Sramek P, Zeman V, Kaminkova J: Immune system of cold-exposed and cold-adapted humans. Eur J Appl Physiol Occup Physiol. 1996, 72 (5-6): 445-450. 10.1007/BF00242274.PubMedGoogle Scholar
  13. Brenner IK, Castellani JW, Gabaree C, Young AJ, Zamecnik J, Shephard RJ, Shek PN: Immune changes in humans during cold exposure: effects of prior heating and exercise. J Appl Physiol. 1999, 87 (2): 699-710.PubMedGoogle Scholar
  14. Aviles H, Johnson MT, Monroy FP: Effects of cold stress on spleen cell proliferation and cytokine production during chronic Toxoplasma gondii infection. Neuroimmunomodulation. 2004, 11 (2): 93-102. 10.1159/000075318.PubMedGoogle Scholar
  15. Jansky L, Sramek P, Savlikova J, Ulicny B, Janakova H, Horky K: Change in sympathetic activity, cardiovascular functions and plasma hormone concentrations due to cold water immersion in men. Eur J Appl Physiol Occup Physiol. 1996, 74 (1-2): 148-152. 10.1007/BF00376507.PubMedGoogle Scholar
  16. Nakamoto M: Responses of sympathetic nervous system to cold exposure in vibration syndrome subjects and age-matched healthy controls. Int Arch Occup Environ Health. 1990, 62 (2): 177-181. 10.1007/BF00383595.PubMedGoogle Scholar
  17. Nakane T, Audhya T, Kanie N, Hollander CS: Evidence for a role of endogenous corticotropin-releasing factor in cold, ether, immobilization, and traumatic stress. Proc Natl Acad Sci U S A. 1985, 82 (4): 1247-1251. 10.1073/pnas.82.4.1247.PubMedPubMed CentralGoogle Scholar
  18. Giagnoni G, Santagostino A, Senini R, Fumagalli P, Gori E: Cold stress in the rat induces parallel changes in plasma and pituitary levels of endorphin and ACTH. Pharmacol Res Commun. 1983, 15 (1): 15-21. 10.1016/S0031-6989(83)80076-9.PubMedGoogle Scholar
  19. Reed HL, Quesada M, Hesslink RL, D'Alesandro MM, Hays MT, Christopherson RJ, Turner BV, Young BA: Changes in serum triiodothyronine kinetics and hepatic type I 5'-deiodinase activity of cold-exposed swine. Am J Physiol. 1994, 266 (5 Pt 1): E786-95.PubMedGoogle Scholar
  20. Quintanar-Stephano JL, Quintanar-Stephano A, Castillo-Hernandez L: Effect of the exposure to chronic-intermittent cold on the thyrotropin and thyroid hormones in the rat. Cryobiology. 1991, 28 (4): 400-403. 10.1016/0011-2240(91)90047-R.PubMedGoogle Scholar
  21. Wallace ME, Smyth MJ: The role of natural killer cells in tumor control--effectors and regulators of adaptive immunity. Springer Semin Immunopathol. 2005, 27 (1): 49-64. 10.1007/s00281-004-0195-x.PubMedGoogle Scholar
  22. Knutson KL, Disis ML: Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother. 2005, 54 (8): 721-728. 10.1007/s00262-004-0653-2.PubMedGoogle Scholar
  23. Metzger D, Zwingmann C, Protz W, Jackel WH: Whole-body cryotherapy in rehabilitation of patients with rheumatoid diseases--pilot study. Rehabilitation (Stuttg). 2000, 39 (2): 93-100.Google Scholar
  24. Holloszy JO, Smith EK: Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory". J Appl Physiol. 1986, 61 (5): 1656-1660.PubMedGoogle Scholar
  25. Panelli MC, White R, Foster M, Martin B, Wang E, Smith K, Marincola FM: Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med. 2004, 2 (1): 17-10.1186/1479-5876-2-17.PubMedPubMed CentralGoogle Scholar
  26. Tamakawa N, Saio M, Suwa T, Ohe N, Yoshimura S, Iwama T, Shinoda J, Sakai N, Takami T: Interleukin-2 activated microglia engulf tumor infiltrating T cells in the central nervous system. Int J Mol Med. 2004, 13 (4): 497-503.PubMedGoogle Scholar
  27. Koneru M, Schaer D, Monu N, Ayala A, Frey AB: Defective proximal TCR signaling inhibits CD8+ tumor-infiltrating lymphocyte lytic function. J Immunol. 2005, 174 (4): 1830-1840.PubMedGoogle Scholar
  28. Radoja S, Saio M, Schaer D, Koneru M, Vukmanovic S, Frey AB: CD8(+) tumor-infiltrating T cells are deficient in perforin-mediated cytolytic activity due to defective microtubule-organizing center mobilization and lytic granule exocytosis. J Immunol. 2001, 167 (9): 5042-5051.PubMedGoogle Scholar
  29. Sramek P, Simeckova M, Jansky L, Savlikova J, Vybiral S: Human physiological responses to immersion into water of different temperatures. Eur J Appl Physiol. 2000, 81 (5): 436-442. 10.1007/s004210050065.PubMedGoogle Scholar
  30. Goundasheva D, Andonova M, Ivanov V: Changes in some parameters of the immune response in rats after cold stress. Zentralbl Veterinarmed B. 1994, 41 (10): 670-674.PubMedGoogle Scholar
  31. Ohno H, Yahata T, Yamashita K, Kuroshima A: Effect of acute cold exposure on ACTH and zinc concentrations in human plasma. Jpn J Physiol. 1987, 37 (4): 749-755.PubMedGoogle Scholar
  32. Vaswani KK, Richard CW, Tejwani GA: Cold swim stress-induced changes in the levels of opioid peptides in the rat CNS and peripheral tissues. Pharmacol Biochem Behav. 1988, 29 (1): 163-168. 10.1016/0091-3057(88)90290-0.PubMedGoogle Scholar
  33. Gerra G, Volpi R, Delsignore R, Maninetti L, Caccavari R, Vourna S, Maestri D, Chiodera P, Ugolotti G, Coiro V: Sex-related responses of beta-endorphin, ACTH, GH and PRL to cold exposure in humans. Acta Endocrinol (Copenh). 1992, 126 (1): 24-28.Google Scholar
  34. Koska J, Ksinantova L, Sebokova E, Kvetnansky R, Klimes I, Chrousos G, Pacak K: Endocrine regulation of subcutaneous fat metabolism during cold exposure in humans. Ann N Y Acad Sci. 2002, 967: 500-505.PubMedGoogle Scholar
  35. Kioukia-Fougia N, Antoniou K, Bekris S, Liapi C, Christofidis I, Papadopoulou-Daifoti Z: The effects of stress exposure on the hypothalamic-pituitary-adrenal axis, thymus, thyroid hormones and glucose levels. Prog Neuropsychopharmacol Biol Psychiatry. 2002, 26 (5): 823-830. 10.1016/S0278-5846(01)00297-4.PubMedGoogle Scholar
  36. Hatfield SM, Petersen BH, DiMicco JA: Beta adrenoceptor modulation of the generation of murine cytotoxic T lymphocytes in vitro. J Pharmacol Exp Ther. 1986, 239 (2): 460-466.PubMedGoogle Scholar
  37. Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M: Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun. 1996, 10 (2): 77-91. 10.1006/brbi.1996.0009.PubMedGoogle Scholar
  38. Kappel M, Poulsen TD, Galbo H, Pedersen BK: Effects of elevated plasma noradrenaline concentration on the immune system in humans. Eur J Appl Physiol Occup Physiol. 1998, 79 (1): 93-98. 10.1007/s004210050479.PubMedGoogle Scholar
  39. Swanson MA, Lee WT, Sanders VM: IFN-gamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. J Immunol. 2001, 166 (1): 232-240.PubMedGoogle Scholar
  40. Madden KS, Felten SY, Felten DL, Sundaresan PR, Livnat S: Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav Immun. 1989, 3 (1): 72-89. 10.1016/0889-1591(89)90007-X.PubMedGoogle Scholar
  41. Moshel YA, Durkin HG, Amassian VE: Lateralized neocortical control of T lymphocyte export from the thymus I. Increased export after left cortical stimulation in behaviorally active rats, mediated by sympathetic pathways in the upper spinal cord. J Neuroimmunol. 2005, 158 (1-2): 3-13. 10.1016/j.jneuroim.2004.09.012.PubMedGoogle Scholar
  42. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES: The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000, 52 (4): 595-638.PubMedGoogle Scholar
  43. Sundaresan G, Suthanthirarajan N, Namasivayam A: Certain immunological parameters in subacute cold stress. Indian J Physiol Pharmacol. 1990, 34 (1): 57-60.PubMedGoogle Scholar
  44. Schedlowski M, Hosch W, Oberbeck R, Benschop RJ, Jacobs R, Raab HR, Schmidt RE: Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms. J Immunol. 1996, 156 (1): 93-99.PubMedGoogle Scholar
  45. Castellani JW, IK MB, Rhind SG: Cold exposure: human immune responses and intracellular cytokine expression. Med Sci Sports Exerc. 2002, 34 (12): 2013-2020. 10.1097/00005768-200212000-00023.PubMedGoogle Scholar
  46. Kenunen OG, Prakh'e IV, Kozlovskii BL: A change in the alarm level entails a change in behavioural strategy of mice in stress and a change in analgesia induced by it. Ross Fiziol Zh Im I M Sechenova. 2004, 90 (12): 1555-1562.PubMedGoogle Scholar
  47. LaFoy J, Geden EA: Postepisiotomy pain: warm versus cold sitz bath. J Obstet Gynecol Neonatal Nurs. 1989, 18 (5): 399-403. 10.1111/j.1552-6909.1989.tb00493.x.PubMedGoogle Scholar
  48. Julien N, Marchand S: Endogenous pain inhibitory systems activated by spatial summation are opioid-mediated. Neurosci Lett. 2006, 401 (3): 256-260. 10.1016/j.neulet.2006.03.032.PubMedGoogle Scholar
  49. Misasi S, Morin G, Kemler D, Olmstead PS, Pryzgocki K: The effect of a toe cap and bias on perceived pain during cold water immersion. J Athl Train. 1995, 30 (1): 49-52.PubMedPubMed CentralGoogle Scholar
  50. Day MP: Hypothermia: a hazard for all seasons. Nursing. 2006, 36 (12 Pt.1): 44-47.PubMedGoogle Scholar
  51. McCullough L, Arora S: Diagnosis and treatment of hypothermia. Am Fam Physician. 2004, 70 (12): 2325-2332.PubMedGoogle Scholar
  52. Tikuisis P: Heat balance precedes stabilization of body temperatures during cold water immersion. J Appl Physiol. 2003, 95 (1): 89-96.PubMedGoogle Scholar
  53. Doufas AG, Sessler DI: Physiology and clinical relevance of induced hypothermia. Neurocrit Care. 2004, 1 (4): 489-498. 10.1385/NCC:1:4:489.PubMedGoogle Scholar
  54. Milo-Cotter O, Setter I, Uriel N, Kaluski E, Vered Z, Golik A, Cotter G: The daily incidence of acute heart failure is correlated with low minimal night temperature: cold immersion pulmonary edema revisited?. J Card Fail. 2006, 12 (2): 114-119. 10.1016/j.cardfail.2005.09.006.PubMedGoogle Scholar
  55. Myint PK, Vowler SL, Woodhouse PR, Redmayne O, Fulcher RA: Winter excess in hospital admissions, in-patient mortality and length of acute hospital stay in stroke: a hospital database study over six seasonal years in Norfolk, UK. Neuroepidemiology. 2007, 28 (2): 79-85. 10.1159/000098550.PubMedGoogle Scholar
  56. Sheth T, Nair C, Muller J, Yusuf S: Increased winter mortality from acute myocardial infarction and stroke: the effect of age. J Am Coll Cardiol. 1999, 33 (7): 1916-1919. 10.1016/S0735-1097(99)00137-0.PubMedGoogle Scholar
  57. Doubt TJ, Mayers DL, Flynn ET: Transient cardiac sinus dysrhythmia occurring after cold water immersion. Am J Cardiol. 1987, 59 (15): 1421-1422. 10.1016/0002-9149(87)90934-9.PubMedGoogle Scholar
  58. Houdas Y, Deklunder G, Lecroart JL: Cold exposure and ischemic heart disease. Int J Sports Med. 1992, 13 Suppl 1: S179-81.PubMedGoogle Scholar
  59. Lader EW, Kronzon I: Ice-water-induced arrhythmias in a patient with ischemic heart disease. Ann Intern Med. 1982, 96 (5): 614-615.PubMedGoogle Scholar
  60. Fiore AE, Shay DK, Haber P, Iskander JK, Uyeki TM, Mootrey G, Bresee JS, Cox NJ: Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep. 2007, 56 (RR-6): 1-54.PubMedGoogle Scholar
  61. Reichert TA, Simonsen L, Sharma A, Pardo SA, Fedson DS, Miller MA: Influenza and the winter increase in mortality in the United States, 1959-1999. Am J Epidemiol. 2004, 160 (5): 492-502. 10.1093/aje/kwh227.PubMedGoogle Scholar
  62. Davis MS, Williams CC, Meinkoth JH, Malayer JR, Royer CM, Williamson KK, McKenzie EC: Influx of neutrophils and persistence of cytokine expression in airways of horses after performing exercise while breathing cold air. Am J Vet Res. 2007, 68 (2): 185-189. 10.2460/ajvr.68.2.185.PubMedGoogle Scholar
  63. Roeggla M, Roeggla G, Seidler D, Muellner M, Laggner AN: Self-limiting pulmonary edema with alveolar hemorrhage during diving in cold water. Am J Emerg Med. 1996, 14 (3): 333-10.1016/S0735-6757(96)90192-8.PubMedGoogle Scholar
  64. Biswas R, Shibu PK, James CM: Pulmonary oedema precipitated by cold water swimming. Br J Sports Med. 2004, 38 (6): e36-10.1136/bjsm.2004.012138.PubMedPubMed CentralGoogle Scholar
  65. Wilmshurst PT: Pulmonary oedema induced by emotional stress, by sexual intercourse, and by exertion in a cold environment in people without evidence of heart disease. Heart. 2004, 90 (7): 806-807. 10.1136/hrt.2002.005595.PubMedPubMed CentralGoogle Scholar
  66. Arican N, Kaya M, Kalayci R, Kucuk M, Cimen V, Elmas I: Effects of acute cold exposure on blood-brain barrier permeability in acute and chronic hyperglycemic rats. Forensic Sci Int. 2002, 125 (2-3): 137-141. 10.1016/S0379-0738(01)00629-6.PubMedGoogle Scholar
  67. Ben-Nathan D, Lustig S, Danenberg HD: Stress-induced neuroinvasiveness of a neurovirulent noninvasive Sindbis virus in cold or isolation subjected mice. Life Sci. 1991, 48 (15): 1493-1500. 10.1016/0024-3205(91)90187-G.PubMedGoogle Scholar
  68. Ben-Nathan D, Lustig S, Feuerstein G: The influence of cold or isolation stress on neuroinvasiveness and virulence of an attenuated variant of West Nile virus. Arch Virol. 1989, 109 (1-2): 1-10. 10.1007/BF01310513.PubMedGoogle Scholar
  69. Ben-Nathan D, Lustig S, Kobiler D, Danenberg HD, Lupu E, Feuerstein G: Dehydroepiandrosterone protects mice inoculated with West Nile virus and exposed to cold stress. J Med Virol. 1992, 38 (3): 159-166. 10.1002/jmv.1890380302.PubMedGoogle Scholar
  70. Wan R, Camandola S, Mattson MP: Dietary supplementation with 2-deoxy-D-glucose improves cardiovascular and neuroendocrine stress adaptation in rats. Am J Physiol Heart Circ Physiol. 2004, 287 (3): H1186-93. 10.1152/ajpheart.00932.2003.PubMedGoogle Scholar
  71. Elmas I, Kucuk M, Kalayci RB, Cevik A, Kaya M: Effects of profound hypothermia on the blood-brain barrier permeability in acute and chronically ethanol treated rats. Forensic Sci Int. 2001, 119 (2): 212-216. 10.1016/S0379-0738(00)00429-1.PubMedGoogle Scholar
  72. Weiss M, Hettmer S, Smith P, Ladisch S: Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase. Cancer Res. 2003, 63 (13): 3654-3658.PubMedGoogle Scholar
  73. Radoja S, Rao TD, Hillman D, Frey AB: Mice bearing late-stage tumors have normal functional systemic T cell responses in vitro and in vivo. J Immunol. 2000, 164 (5): 2619-2628.PubMedGoogle Scholar
  74. Glac W, Borman A, Badtke P, Stojek W, Orlikowska A, Tokarski J: Amphetamine enhances Natural Killer cytotoxic activity via beta-adrenergic mechanism. J Physiol Pharmacol. 2006, 57 Suppl 11: 125-132.PubMedGoogle Scholar
  75. Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-Eliyahu S: Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures. Anesth Analg. 2003, 97 (5): 1331-1339. 10.1213/01.ANE.0000082995.44040.07.PubMedGoogle Scholar
  76. Zhang Z, Song Y, Wang XL: Inositol hexaphosphate-induced enhancement of natural killer cell activity correlates with suppression of colon carcinogenesis in rats. World J Gastroenterol. 2005, 11 (32): 5044-5046.PubMedPubMed CentralGoogle Scholar
  77. Afanasyeva M, Wang Y, Kaya Z, Stafford EA, Dohmen KM, Sadighi Akha AA, Rose NR: Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-gamma-independent pathway. Circulation. 2001, 104 (25): 3145-3151. 10.1161/hc5001.100629.PubMedGoogle Scholar
  78. Franch A, Castellote C, Castell M: Blood lymphocyte subsets in rats with adjuvant arthritis. Ann Rheum Dis. 1994, 53 (7): 461-466.PubMedPubMed CentralGoogle Scholar
  79. Biller H, Bade B, Matthys H, Luttmann W, Virchow JC: Interferon-gamma secretion of peripheral blood CD8+ T lymphocytes in patients with bronchial asthma: in vitro stimulus determines cytokine production. Clin Exp Immunol. 2001, 126 (2): 199-205. 10.1046/j.1365-2249.2001.01666.x.PubMedPubMed CentralGoogle Scholar
  80. Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, Wagner DD: Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood. 2006, 107 (2): 591-593. 10.1182/blood-2005-06-2506.PubMedPubMed CentralGoogle Scholar
  81. Vorbrodt AW, Dobrogowska DH, Lossinsky AS: Ultracytochemical studies of the effects of aluminum on the blood-brain barrier of mice. J Histochem Cytochem. 1994, 42 (2): 203-212.PubMedGoogle Scholar
  82. Marino F, Sockler JM, Fry JM: Thermoregulatory, metabolic and sympathoadrenal responses to repeated brief exposure to cold. Scand J Clin Lab Invest. 1998, 58 (7): 537-545. 10.1080/00365519850186157.PubMedGoogle Scholar
  83. Smith DJ, Deuster PA, Ryan CJ, Doubt TJ: Prolonged whole body immersion in cold water: hormonal and metabolic changes. Undersea Biomed Res. 1990, 17 (2): 139-147.PubMedGoogle Scholar
  84. Makarova OV, Trunova GV, Diatroptov ME, Serebryakov SN, Kondashevskaya MV, Malaitsev VV: Comparative characterization of cytokine production by concanavalin A-activated splenocytes from BALB/c and C57BL/6 mice after cold exposure. Bull Exp Biol Med. 2005, 139 (2): 220-222. 10.1007/s10517-005-0253-y.PubMedGoogle Scholar
  85. Liu YL, Bi H, Chi SM, Fan R, Wang YM, Ma XL, Chen YM, Luo WJ, Pei JM, Chen JY: The effect of compound nutrients on stress-induced changes in serum IL-2, IL-6 and TNF-alpha levels in rats. Cytokine. 2007, 37 (1): 14-21. 10.1016/j.cyto.2007.02.009.PubMedGoogle Scholar
  86. DeKrey GK, Kerkvliet NI: Effects of exogenous corticosterone treatment on alloantigen-specific cytotoxic T lymphocyte activity in mice. J Pharmacol Exp Ther. 1995, 273 (2): 823-829.PubMedGoogle Scholar
  87. Wiegers GJ, Stec IE, Klinkert WE, Linthorst AC, Reul JM: Bidirectional effects of corticosterone on splenic T-cell activation: critical role of cell density and culture time. Neuroendocrinology. 2001, 73 (2): 139-148. 10.1159/000054630.PubMedGoogle Scholar
  88. Gonsalkorale WM, Dascombe MJ, Hutchinson IV: Adrenocorticotropic hormone as a potential enhancer of T-lymphocyte function in the rat mixed lymphocyte reaction. Int J Immunopharmacol. 1995, 17 (3): 197-206. 10.1016/0192-0561(94)00101-S.PubMedGoogle Scholar
  89. Johnson EW, Hughes TK, Smith EM: ACTH enhancement of T-lymphocyte cytotoxic responses. Cell Mol Neurobiol. 2005, 25 (3-4): 743-757. 10.1007/s10571-005-3972-8.PubMedGoogle Scholar
  90. Aoki N, Wakisaka G, Nagata I: Effects of thyroxine on T-cell counts and tumour cell rejection in mice. Acta Endocrinol (Copenh). 1976, 81 (1): 104-109.Google Scholar
  91. Jin X, Zhao H, Wang JF, Fang LB, Lin JY, Gao Y: Influence of beta-endorphin on function of immune system of patients with cerebral hemorrhage. Zhonghua Yi Xue Za Zhi. 2003, 83 (16): 1409-1412.PubMedGoogle Scholar
  92. Boyadjieva NI, Dokur M, Advis JP, Meadows GG, Sarkar DK: Beta-endorphin modulation of lymphocyte proliferation: effects of ethanol. Alcohol Clin Exp Res. 2002, 26 (11): 1719-1727.PubMedGoogle Scholar
  93. Mirandola P, Ponti C, Gobbi G, Sponzilli I, Melloni E, Vitale M: The response of human natural killer cells to interleukin-2. J Endocrinol Invest. 2004, 27 (6 Suppl): 146-150.PubMedGoogle Scholar
  94. Mariani E, Ravaglia G, Forti P, Meneghetti A, Tarozzi A, Maioli F, Boschi F, Pratelli L, Pizzoferrato A, Piras F, Facchini A: Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians. Clin Exp Immunol. 1999, 116 (1): 19-27. 10.1046/j.1365-2249.1999.00855.x.PubMedPubMed CentralGoogle Scholar
  95. Watanabe K, Iwatani Y, Hidaka Y, Watanabe M, Amino N: Long-term effects of thyroid hormone on lymphocyte subsets in spleens and thymuses of mice. Endocr J. 1995, 42 (5): 661-668.PubMedGoogle Scholar
  96. Spengler RN, Allen RM, Remick DG, Strieter RM, Kunkel SL: Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. J Immunol. 1990, 145 (5): 1430-1434.PubMedGoogle Scholar
  97. Le Tulzo Y, Shenkar R, Kaneko D, Moine P, Fantuzzi G, Dinarello CA, Abraham E: Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression. J Clin Invest. 1997, 99 (7): 1516-1524.PubMedPubMed CentralGoogle Scholar
  98. Livnat S, Madden KS, Felten DL, Felten SY: Regulation of the immune system by sympathetic neural mechanisms. Prog Neuropsychopharmacol Biol Psychiatry. 1987, 11 (2-3): 145-152. 10.1016/0278-5846(87)90052-2.PubMedGoogle Scholar
  99. Navolotskaya EV, Malkova NV, Zargarova TA, Lepikhova TN, Krasnova SB, Lipkin VM: Effect of synthetic beta-endorphin-like peptide immunorphin on human T lymphocytes. Biochemistry (Mosc). 2002, 67 (3): 357-363. 10.1023/A:1014844718799.Google Scholar
  100. Fattorossi A, Matricardi PM, Pizzolo JG, Le Moli S, Antonelli G, D'Amelio R: Lack of specificity in the mechanisms involved in the enhancement of the concanavalin A driven human T lymphocyte stimulation by beta-endorphin: studies on activation marker expression, cell cycle and interleukin release. J Biol Regul Homeost Agents. 1991, 5 (3): 91-97.PubMedGoogle Scholar
  101. Hemmick LM, Bidlack JM: Beta-endorphin stimulates rat T lymphocyte proliferation. J Neuroimmunol. 1990, 29 (1-3): 239-248. 10.1016/0165-5728(90)90167-L.PubMedGoogle Scholar
  102. Balazs C, Leovey A, Szabo M, Bako G: Stimulating effect of triiodothyronine on cell-mediated immunity. Eur J Clin Pharmacol. 1980, 17 (1): 19-23. 10.1007/BF00561672.PubMedGoogle Scholar
  103. Ong ML, Malkin DG, Malkin A: Alteration of lymphocyte reactivities by thyroid hormones. Int J Immunopharmacol. 1986, 8 (7): 755-762. 10.1016/0192-0561(86)90012-3.PubMedGoogle Scholar
  104. Klecha AJ, Barreiro Arcos ML, Genaro AM, Gorelik G, Silberman DM, Caro R, Cremaschi GA: Different mitogen-mediated beta-adrenergic receptor modulation in murine T lymphocytes depending on the thyroid status. Neuroimmunomodulation. 2005, 12 (2): 92-99. 10.1159/000083581.PubMedGoogle Scholar
  105. Messingham KA, Shirazi M, Duffner LA, Emanuele MA, Kovacs EJ: Testosterone receptor blockade restores cellular immunity in male mice after burn injury. J Endocrinol. 2001, 169 (2): 299-308. 10.1677/joe.0.1690299.PubMedGoogle Scholar
  106. Benten WP, Bettenhaeuser U, Wunderlich F, Van Vliet E, Mossmann H: Testosterone-induced abrogation of self-healing of Plasmodium chabaudi malaria in B10 mice: mediation by spleen cells. Infect Immun. 1991, 59 (12): 4486-4490.PubMedPubMed CentralGoogle Scholar
  107. Maccio DR, Calfa G, Roth GA: Oral testosterone in male rats and the development of experimental autoimmune encephalomyelitis. Neuroimmunomodulation. 2005, 12 (4): 246-254. 10.1159/000085656.PubMedGoogle Scholar
  108. Lu Y, Tang M, Wasserfall C, Kou Z, Campbell-Thompson M, Gardemann T, Crawford J, Atkinson M, Song S: Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice. Hum Gene Ther. 2006, 17 (6): 625-634. 10.1089/hum.2006.17.625.PubMedGoogle Scholar
  109. Gilmore W, Weiner LP: Beta-endorphin enhances interleukin-2 (IL-2) production in murine lymphocytes. J Neuroimmunol. 1988, 18 (2): 125-138. 10.1016/0165-5728(88)90061-6.PubMedGoogle Scholar
  110. Chiappelli F, Yamashita N, Faisal M, Kemeny M, Bullington R, Nguyen L, Clement LT, Fahey JL: Differential effect of beta-endorphin on three human cytotoxic cell populations. Int J Immunopharmacol. 1991, 13 (2-3): 291-297.PubMedGoogle Scholar
  111. Hajkova R, Indrova M, Jandlova T, Bubenik J, Reinis M: Interleukin 2 gene therapy of surgical minimal residual tumour disease: characterization of cytolytic effector cells from tumour progressors and regressors. Folia Biol (Praha). 1999, 45 (6): 227-231.Google Scholar
  112. Palmer PA, Scharenberg JG, von Blomberg BM, Stam AG, Meijer CJ, Roest GJ, Franks CR, Scheper RJ: Persistent augmentation of natural-killer- and T-cell-mediated cytotoxicity in peripheral blood mononuclear cells pulsed in vitro with high-dose recombinant interleukin-2 prior to culturing with a low maintenance dose. Cancer Immunol Immunother. 1994, 39 (1): 34-40.PubMedGoogle Scholar
  113. Euhus DM, Kimura L, Arnold B: Expansion of CD3+CD56+ lymphocytes correlates with induction of cytotoxicity by interleukin-2 gene transfer in human breast tumor cultures. Ann Surg Oncol. 1997, 4 (5): 432-439. 10.1007/BF02305558.PubMedGoogle Scholar
  114. Katz A, Shulman LM, Porgador A, Revel M, Feldman M, Eisenbach L: Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy. J Immunother Emphasis Tumor Immunol. 1993, 13 (2): 98-109.PubMedGoogle Scholar
  115. Lee TY, Koo AS, Peyret C, Shimabukuro T, Dekernion JB, Belldegrun A: The effects of interleukin-6 on tumor-infiltrating lymphocytes derived from human renal cell cancer. J Urol. 1991, 145 (3): 663-667.PubMedGoogle Scholar
  116. Charnetsky PS, Greisman RA, Salmon SE, Hersh EM, Scuderi P: Increased peripheral blood leukocyte cytotoxic activity in cancer patients during the continuous intravenous administration of recombinant human tumor necrosis factor. J Clin Immunol. 1989, 9 (1): 34-38. 10.1007/BF00917125.PubMedGoogle Scholar
  117. Yoshida J, Takaoka T, Mizuno M, Momota H, Okada H: Cytolysis of malignant glioma cells by lymphokine-activated killer cells combined with anti-CD3/antiglioma bifunctional antibody and tumor necrosis factor-alpha. J Surg Oncol. 1996, 62 (3): 177-182. 10.1002/(SICI)1096-9098(199607)62:3<177::AID-JSO6>3.0.CO;2-4.PubMedGoogle Scholar
  118. Philip R: Cytolysis of tumor necrosis factor (TNF)-resistant tumor targets. Differential cytotoxicity of monocytes activated by the interferons, IL-2, and TNF. J Immunol. 1988, 140 (4): 1345-1349.PubMedGoogle Scholar
  119. Stringfellow MM, Wilson RE, Herrmann SH: Production of interleukin-6 in vitro parallels development of cytotoxic T lymphocytes from murine thymocytes. Surgery. 1989, 106 (2): 332-338.PubMedGoogle Scholar
  120. Galandrini R, Cernetti C, Albi N, Dembech C, Terenzi A, Grignani F, Velardi A: Interleukin-6 is constitutively produced by human CTL clones and is required to maintain their cytolytic function. Cell Immunol. 1991, 138 (1): 11-23. 10.1016/0008-8749(91)90128-X.PubMedGoogle Scholar
  121. Stolfi VM, Milsom JW, Finke JH, Fazio VW, Fiocchi C: Resident research award: tumor necrosis factor alpha selectively enhances growth and cytotoxic activity of tumor infiltrating lymphocytes from human colorectal cancer. J Surg Res. 1992, 52 (1): 39-45.PubMedGoogle Scholar
  122. Breit SN, Wakefield D, Robinson JP, Luckhurst E, Clark P, Penny R: The role of alpha 1-antitrypsin deficiency in the pathogenesis of immune disorders. Clin Immunol Immunopathol. 1985, 35 (3): 363-380. 10.1016/0090-1229(85)90097-2.PubMedGoogle Scholar
  123. Grossi P, Dughetti S, Di Perri G, Vento S, Mondelli M: Direct immune response against hepatic antigens in patients with alpha-1-antitrypsin deficiency. Boll Ist Sieroter Milan. 1986, 65 (2): 143-149.PubMedGoogle Scholar
  124. Jonsdottir IH, Johansson C, Asea A, Hellstrand K, Thoren P, Hoffmann P: Chronic intracerebroventricular administration of beta-endorphin augments natural killer cell cytotoxicity in rats. Regul Pept. 1996, 62 (2-3): 113-118. 10.1016/0167-0115(96)00007-9.PubMedGoogle Scholar
  125. Dokur M, Chen CP, Advis JP, Sarkar DK: Beta-endorphin modulation of interferon-gamma, perforin and granzyme B levels in splenic NK cells: effects of ethanol. J Neuroimmunol. 2005, 166 (1-2): 29-38. 10.1016/j.jneuroim.2005.03.015.PubMedGoogle Scholar
  126. Boyadjieva N, Advis JP, Sarkar DK: Role of beta-endorphin, corticotropin-releasing hormone, and autonomic nervous system in mediation of the effect of chronic ethanol on natural killer cell cytolytic activity. Alcohol Clin Exp Res. 2006, 30 (10): 1761-1767. 10.1111/j.1530-0277.2006.00209.x.PubMedGoogle Scholar
  127. Gatti G, Masera RG, Pallavicini L, Sartori ML, Staurenghi A, Orlandi F, Angeli A: Interplay in vitro between ACTH, beta-endorphin, and glucocorticoids in the modulation of spontaneous and lymphokine-inducible human natural killer (NK) cell activity. Brain Behav Immun. 1993, 7 (1): 16-28. 10.1006/brbi.1993.1002.PubMedGoogle Scholar
  128. Martinez-Taboada V, Bartolome MJ, Amado JA, Blanco R, Garcia-Unzueta MT, Rodriguez-Valverde V, Lopez-Hoyos M: Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic-pituitary-adrenal axis. Mech Ageing Dev. 2002, 123 (11): 1477-1486. 10.1016/S0047-6374(02)00116-1.PubMedGoogle Scholar
  129. Kmiec Z, Mysliwska J, Rachon D, Kotlarz G, Sworczak K, Mysliwski A: Natural killer activity and thyroid hormone levels in young and elderly persons. Gerontology. 2001, 47 (5): 282-288. 10.1159/000052813.PubMedGoogle Scholar
  130. Ingram KG, Crouch DA, Douez DL, Croy BA, Woodward B: Effects of triiodothyronine supplements on splenic natural killer cells in malnourished weanling mice. Int J Immunopharmacol. 1995, 17 (1): 21-32. 10.1016/0192-0561(94)00079-4.PubMedGoogle Scholar
  131. Provinciali M, Muzzioli M, Fabris N: Thyroxine-dependent modulation of natural killer activity. J Exp Pathol. 1987, 3 (4): 617-622.PubMedGoogle Scholar
  132. Provinciali M, Muzzioli M, Di Stefano G, Fabris N: Recovery of spleen cell natural killer activity by thyroid hormone treatment in old mice. Nat Immun Cell Growth Regul. 1991, 10 (4): 226-236.PubMedGoogle Scholar
  133. Saito T, Otsuka A, Kurashima A, Watanabe M, Aoki S, Harada A: Study of lymphocyte and NK cell activity during mild hypothermia therapy. No Shinkei Geka. 2001, 29 (7): 633-639.PubMedGoogle Scholar
  134. Jiang XH, Guo SY, Xu S, Yin QZ, Ohshita Y, Naitoh M, Horibe Y, Hisamitsu T: Sympathetic nervous system mediates cold stress-induced suppression of natural killer cytotoxicity in rats. Neurosci Lett. 2004, 358 (1): 1-4. 10.1016/j.neulet.2003.11.007.PubMedGoogle Scholar
  135. Kalinichenko VV, Mokyr MB, Graf LH, Cohen RL, Chambers DA: Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression. J Immunol. 1999, 163 (5): 2492-2499.PubMedGoogle Scholar
  136. Shakhar G, Ben-Eliyahu S: In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J Immunol. 1998, 160 (7): 3251-3258.PubMedGoogle Scholar

Copyright

© Shevchuk and Radoja; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.