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Physiol. Rev. 71: 93-127, 1991;
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Physiological Reviews, Vol 71, 93-127, Copyright © 1991 by American Physiological Society

JOURNAL ARTICLE

Fever: role of pyrogens and cryogens

M. J. Kluger
Department of Physiology, University of Michigan Medical School, Ann Arbor.

The biology of cytokines is one of the most rapidly growing areas of biomedical research. It is understandable why the assumption was made several years ago that EP was equivalent to IL-1 (both alpha and beta) and subsequently to IL-1 alpha, IL-1 beta, and TNF. However, as more data have been obtained, it has become clearer that many cytokines and hormones are capable of participating in the febrile response. It is also becoming apparent that EPs and ECs might influence body temperature during nonpathological states, perhaps contributing to the elevation in temperature during or after exercise, the circadian variation in temperature, and others. Medical textbooks have begun to list IL-1 as the EP. As I attempted to make clear in this review, evidence that IL-1 alpha is a circulating EP is poor. The evidence is considerably stronger that IL-1 beta is an EP, at least during LPS-induced fever in rodents. The point I have tried to emphasize is that before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one. As summarized in Tables 4 and 5, there are many candidates for EPs and ECs, but much more experimental evidence is essential before we gain a clear understanding of the relationship between contact with an exogenous pyrogen, the release of EPs and ECs, and the development of fever.


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 CVIHome page
Y. Nakagawa, H. Maeda, and T. Murai
Evaluation of the In Vitro Pyrogen Test System Based on Proinflammatory Cytokine Release from Human Monocytes: Comparison with a Human Whole Blood Culture Test System and with the Rabbit Pyrogen Test
Clin. Vaccine Immunol., May 1, 2002; 9(3): 588 - 597.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
A. A. Steiner, J. Antunes-Rodrigues, S. M. McCann, and L. G. S. Branco
Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R584 - R593.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Hosoi, Y. Okuma, A. Ono, and Y. Nomura
Subdiaphragmatic vagotomy fails to inhibit intravenous leptin-induced IL-1beta expression in the hypothalamus
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R627 - R631.
[Abstract] [Full Text] [PDF]

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 Pharmacol. Rev.Home page
A. P. Kohm and V. M. Sanders
Norepinephrine and beta 2-Adrenergic Receptor Stimulation Regulate CD4+ T and B Lymphocyte Function in Vitro and in Vivo
Pharmacol. Rev., December 1, 2001; 53(4): 487 - 525.
[Abstract] [Full Text] [PDF]

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 Innate ImmunityHome page
A. N. Azab and J. Kaplanski
Vagotomy attenuates the effect of lipopolysaccharide on body temperature of rats in a dose-dependent manner
Innate Immunity, October 1, 2001; 7(5): 359 - 364.
[Abstract] [PDF]

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 J. Immunol.Home page
J. R. Ostberg, C. Gellin, R. Patel, and E. A. Repasky
Regulatory Potential of Fever-Range Whole Body Hyperthermia on Langerhans Cells and Lymphocytes in an Antigen-Dependent Cellular Immune Response
J. Immunol., September 1, 2001; 167(5): 2666 - 2670.
[Abstract] [Full Text] [PDF]

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 PediatricsHome page
M. Crocetti, N. Moghbeli, and J. Serwint
Fever Phobia Revisited: Have Parental Misconceptions About Fever Changed in 20 Years?
Pediatrics, June 1, 2001; 107(6): 1241 - 1246.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
N. C. Staub Sr., K. E. Longworth, V. Serikov, E. H. Jerome, and T. Elsasser
Detergent inhibits 70-90% of responses to intravenous endotoxin in awake sheep
J Appl Physiol, May 1, 2001; 90(5): 1788 - 1797.
[Abstract] [Full Text] [PDF]

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 Psychosom. Med.Home page
L. Capuron, A. Ravaud, and R. Dantzer
Timing and Specificity of the Cognitive Changes Induced by Interleukin-2 and Interferon-{alpha} Treatments in Cancer Patients
Psychosom Med, May 1, 2001; 63(3): 376 - 386.
[Abstract] [Full Text] [PDF]

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 Psychosom. Med.Home page
T. Oka, K. Oka, and T. Hori
Mechanisms and Mediators of Psychological Stress-Induced Rise in Core Temperature
Psychosom Med, May 1, 2001; 63(3): 476 - 486.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
L. E. Goehler, R. P. A. Gaykema, M. K. Hansen, J. L. Kleiner, S. F. Maier, and L. R. Watkins
Staphylococcal enterotoxin B induces fever, brain c-Fos expression, and serum corticosterone in rats
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1434 - R1439.
[Abstract] [Full Text] [PDF]

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 BloodHome page
S. S. Evans, W.-C. Wang, M. D. Bain, R. Burd, J. R. Ostberg, and E. A. Repasky
Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules
Blood, May 1, 2001; 97(9): 2727 - 2733.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
K. Yamagata, K. Matsumura, W. Inoue, T. Shiraki, K. Suzuki, S. Yasuda, H. Sugiura, C. Cao, Y. Watanabe, and S. Kobayashi
Coexpression of Microsomal-Type Prostaglandin E Synthase with Cyclooxygenase-2 in Brain Endothelial Cells of Rats during Endotoxin-Induced Fever
J. Neurosci., April 15, 2001; 21(8): 2669 - 2677.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
M. Josa, J. P. Urizar, J. Rapado, C. Dios-Viéitez, G. Castañeda-Hernández, F. Flores-Murrieta, M. J. Renedo, and I. F. Trocóniz
Pharmacokinetic/Pharmacodynamic Modeling of Antipyretic and Anti-Inflammatory Effects of Naproxen in the Rat
J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 198 - 205.
[Abstract] [Full Text]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. K. Hansen, K. A. O'Connor, L. E. Goehler, L. R. Watkins, and S. F. Maier
The contribution of the vagus nerve in interleukin-1{beta}-induced fever is dependent on dose
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2001; 280(4): R929 - R934.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Monroy, J. W. Kuluz, D. He, W. D. Dietrich, and C. L. Schleien
Role of nitric oxide in the cerebrovascular and thermoregulatory response to interleukin-1{beta}
Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1448 - H1453.
[Abstract] [Full Text] [PDF]

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 Emerg. Med. J.Home page
C. J Gordon
The therapeutic potential of regulated hypothermia
Emerg. Med. J., March 1, 2001; 18(2): 81 - 89.
[Abstract] [Full Text]

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 J. Physiol.Home page
T Cartmell, G N Luheshi, S J Hopkins, N J Rothwell, and S Poole
Role of endogenous interleukin-1 receptor antagonist in regulating fever induced by localised inflammation in the rat
J. Physiol., February 15, 2001; 531(1): 171 - 180.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
A. A. Steiner and L. G. S. Branco
Carbon monoxide is the heme oxygenase product with a pyretic action: evidence for a cGMP signaling pathway
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2001; 280(2): R448 - R457.
[Abstract] [Full Text] [PDF]

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 PhysiologyHome page
J. G. Cannon
Inflammatory Cytokines in Nonpathological States
Physiology, December 1, 2000; 15(6): 298 - 303.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
J. R. Ostberg, S. L. Taylor, H. Baumann, and E. A. Repasky
Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response
J. Leukoc. Biol., December 1, 2000; 68(6): 815 - 820.
[Abstract] [Full Text]

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 Exp. Biol. Med.Home page
N. M. Filipov, F. N. Thompson, J. A. Stuedemann, T. H. Elsasser, S. Kahl, L. H. Stanker, C. R. Young, D. L. Dawe, and C. K. Smith
Anti-Inflammatory Effects of Ergotamine in Steers
Experimental Biology and Medicine, November 1, 2000; 225(2): 136 - 142.
[Abstract] [Full Text]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A.-M. Coelho, J. Fioramonti, and L. Bueno
Systemic lipopolysaccharide influences rectal sensitivity in rats: role of mast cells, cytokines, and vagus nerve
Am J Physiol Gastrointest Liver Physiol, October 1, 2000; 279(4): G781 - G790.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Watanabe, M. Hashimoto, M. Wada, T. Imoto, M. Miyoshi, D. Sadamitsu, and T. Maekawa
Angiotensin-converting enzyme inhibitor inhibits dehydration-enhanced fever induced by endotoxin in rats
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1512 - R1516.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
W. Kozak, M. J. Kluger, A. Kozak, M. Wachulec, and K. Dokladny
Role of cytochrome P-450 in endogenous antipyresis
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R455 - R460.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
T Cartmell, S Poole, A V Turnbull, N J Rothwell, and G N Luheshi
Circulating interleukin-6 mediates the febrile response to localised inflammation in rats
J. Physiol., August 1, 2000; 526(3): 653 - 661.
[Abstract] [Full Text] [PDF]

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 Biol Res NursHome page
E. J. Corwin
Understanding Cytokines Part I: Physiology and Mechanism of Action
Biol Res Nurs, July 1, 2000; 2(1): 30 - 40.
[Abstract] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Hosoi, Y. Okuma, and Y. Nomura
Electrical stimulation of afferent vagus nerve induces IL-1beta expression in the brain and activates HPA axis
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2000; 279(1): R141 - R147.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
K. C. Bicego-Nahas, A. A. Steiner, E. C. Carnio, J. Antunes-Rodrigues, and L. G. S. Branco
Antipyretic effect of arginine vasotocin in toads
Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1408 - R1414.
[Abstract] [Full Text] [PDF]

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 JCOHome page
L. Capuron, A. Ravaud, and R. Dantzer
Early Depressive Symptoms in Cancer Patients Receiving Interleukin 2 and/or Interferon Alfa-2b Therapy
J. Clin. Oncol., May 10, 2000; 18(10): 2143 - 2151.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
A. A. Steiner and L. G. S. Branco
Central CO-heme oxygenase pathway raises body temperature by a prostaglandin-independent way
J Appl Physiol, May 1, 2000; 88(5): 1607 - 1613.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
I. R. Pela, M. E. S. Ferreira, M. C. C. Melo, C. A. A. Silva, M. M. Coelho, and C. F. Valenzuela
Evidence that platelet-derived growth factor may be a novel endogenous pyrogen in the central nervous system
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2000; 278(5): R1275 - R1281.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. K. Hansen, K. T. Nguyen, M. Fleshner, L. E. Goehler, R. P. A. Gaykema, S. F. Maier, and L. R. Watkins
Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R331 - R336.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Mizuno, Y. Kannan, M. Tokunaga, M. Moriyama, Y. Kiso, K. Kusakabe, J. Yamate, K. Kiyomiya, and T. Sugano
Role of hypothermia induced by tumor necrosis factor on apoptosis and function of inflammatory neutrophils in mice
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R157 - R165.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. C. Almeida, E. C. Carnio, and L. G. S. Branco
Role of nitric oxide in hypoxia inhibition of fever
J Appl Physiol, December 1, 1999; 87(6): 2186 - 2190.
[Abstract] [Full Text] [PDF]


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