Endocrinology, Vol 126, 2876-2881, Copyright © 1990 by Endocrine Society

ARTICLES

Interactions between tumor necrosis factor-alpha, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat

R Bernardini, TC Kamilaris, AE Calogero, EO Johnson, MT Gomez, PW Gold and GP Chrousos
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.

We studied the effects of tumor necrosis factor-alpha (TNF alpha), a macrophage-derived pleiotropic cytokine produced during the inflammatory/immune response, on the function of the hypothalamic- pituitary-adrenal (HPA) axis of the rat. Intravenous injections of TNF alpha stimulated plasma ACTH and corticosterone secretion in a dose- dependent fashion. This effect was inhibited by a rat CRH antiserum that was administered to the rats 1 h before the TNF alpha injections. This suggested that CRH is a major mediator of the HPA axis response to TNF alpha. We subsequently evaluated the ability of TNF alpha to influence CRH and ACTH secretion in vitro by explanted rat hypothalami in organ culture and by dispersed rat anterior pituicytes in primary culture respectively. Hypothalami were incubated for 40 min with graded concentrations of TNF alpha (10 pM to 1 microM). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 x 10 pM (P less than 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 microM), eicosatetraynoic acid (10 microM), or nordihydroguaiaretic acid (30 microM) resulted in inhibition of TNF alpha-stimulated CRH secretion (P less than 0.05). Interestingly, 4-h incubation with TNF alpha had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNF alpha (100 nM and 1 microM), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNF alpha represents one of the immune response mediators that directly or via stimulation of other cytokines act as activators of the HPA axis during immune/inflammatory reactions. This effect appears to be glucocorticoid suppressible and eicosanoid mediated. The primary site of action of TNF alpha appears to by the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF alpha, however, cannot be excluded.

This article has been cited by other articles:

				E. R. Ropelle, J. R. Pauli, K. G. Zecchin, M. Ueno, C. T. de Souza, J. Morari, M. C. Faria, L. A. Velloso, M. J. A. Saad, and J. B. C. Carvalheira A Central Role for Neuronal Adenosine 5'-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia Endocrinology, November 1, 2007; 148(11): 5220 - 5229. [Abstract] [Full Text] [PDF]

				I. V. Mikhaylova, T. Kuulasmaa, J. Jaaskelainen, and R. Voutilainen Tumor Necrosis Factor-{alpha} Regulates Steroidogenesis, Apoptosis, and Cell Viability in the Human Adrenocortical Cell Line NCI-H295R Endocrinology, January 1, 2007; 148(1): 386 - 392. [Abstract] [Full Text] [PDF]

				E. Roggero, A. R Perez, M. Tamae-Kakazu, I. Piazzon, I. Nepomnaschy, H. O Besedovsky, O. A Bottasso, and A. del Rey Endogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection. J. Endocrinol., August 1, 2006; 190(2): 495 - 503. [Abstract] [Full Text] [PDF]

				M. N. Silverman, A. H. Miller, C. A. Biron, and B. D. Pearce Characterization of an Interleukin-6- and Adrenocorticotropin-Dependent, Immune-to-Adrenal Pathway during Viral Infection Endocrinology, August 1, 2004; 145(8): 3580 - 3589. [Abstract] [Full Text] [PDF]

				S. Kushibiki, K. Hodate, H. Shingu, Y. Obara, E. Touno, M. Shinoda, and Y. Yokomizo Metabolic and Lactational Responses during Recombinant Bovine Tumor Necrosis Factor-{alpha} Treatment in Lactating Cows J Dairy Sci, March 1, 2003; 86(3): 819 - 827. [Abstract] [Full Text] [PDF]

				A. Beishuizen and L. G. Thijs Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis Innate Immunity, February 1, 2003; 9(1): 3 - 24. [Abstract] [PDF]

				M. Kohno, Y. Kawahito, Y. Tsubouchi, A. Hashiramoto, R. Yamada, K.-i. Inoue, Y. Kusaka, T. Kubo, I. J. Elenkov, G. P. Chrousos, et al. Urocortin Expression in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis: Relation to Inflammatory Activity J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4344 - 4352. [Abstract] [Full Text] [PDF]

				J. Dahlgren, C. Nilsson, E. Jennische, H.-P. Ho, E. Eriksson, A. Niklasson, P. Bjorntorp, K. A. Wikland, and A. Holmang Prenatal cytokine exposure results in obesity and gender-specific programming Am J Physiol Endocrinol Metab, August 1, 2001; 281(2): E326 - E334. [Abstract] [Full Text] [PDF]

				S. Rivest, S. Lacroix, L. Vallières, S. Nadeau, J. Zhang, and N. Laflamme How the Blood Talks to the Brain Parenchyma and the Paraventricular Nucleus of the Hypothalamus During Systemic Inflammatory and Infectious Stimuli Experimental Biology and Medicine, January 1, 2000; 223(1): 22 - 38. [Abstract] [Full Text]

				S. Hayley, K. Brebner, S. Lacosta, Z. Merali, and H. Anisman Sensitization to the Effects of Tumor Necrosis Factor-alpha : Neuroendocrine, Central Monoamine, and Behavioral Variations J. Neurosci., July 1, 1999; 19(13): 5654 - 5665. [Abstract] [Full Text] [PDF]

				M. Casadevall, E. Saperas, J. Panes, A. Salas, D. C. Anderson, J. R. Malagelada, and J. M. Pique Mechanisms underlying the anti-inflammatory actions of central corticotropin-releasing factor Am J Physiol Gastrointest Liver Physiol, April 1, 1999; 276(4): G1016 - G1026. [Abstract] [Full Text] [PDF]

				Y. Ohno, M. Fujimoto, A. Nishimura, and N. Aoki Change of Peripheral Levels of Pituitary Hormones and Cytokines after Injection of Interferon (IFN)-{beta} in Patients with Chronic Hepatitis C J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3681 - 3687. [Abstract] [Full Text]

				Y. Shirouzu, K. Shirouzu, and S. Yoshida Effect of fentanyl on morphine levels in the brain in rats receiving intracerebroventricular injection of TNF-alpha Am J Physiol Endocrinol Metab, October 1, 1998; 275(4): E635 - E640. [Abstract] [Full Text] [PDF]

				M. Katahira, Y. Iwasaki, Y. Aoki, Y. Oiso, and H. Saito Cytokine Regulation of the Rat Proopiomelanocortin Gene Expression in AtT-20 Cells Endocrinology, May 1, 1998; 139(5): 2414 - 2422. [Abstract] [Full Text] [PDF]

				A. V. Turnbull and C. L. Rivier Intracerebroventricular Passive Immunization. I. The Effect of Intracerebroventricular Administration of an Antiserum to Tumor Necrosis Factor-{alpha} on the Plasma Adrenocorticotropin Response to Lipopolysaccharide in Rats Endocrinology, January 1, 1998; 139(1): 119 - 127. [Abstract] [Full Text] [PDF]

				A. Ericsson, C. Arias, and P. E. Sawchenko Evidence for an Intramedullary Prostaglandin-Dependent Mechanism in the Activation of Stress-Related Neuroendocrine Circuitry by Intravenous Interleukin-1 J. Neurosci., September 15, 1997; 17(18): 7166 - 7179. [Abstract] [Full Text] [PDF]

				A. V. Turnbull, F. J. Pitossi, J.-J. Lebrun, S. Lee, J. C. Meltzer, D. M. Nance, A. del Rey, H. O. Besedovsky, and C. Rivier Inhibition of Tumor Necrosis Factor-alpha Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats J. Neurosci., May 1, 1997; 17(9): 3262 - 3273. [Abstract] [Full Text] [PDF]

				C. Bousquet, D. W. Ray, and S. Melmed A Common Pro-opiomelanocortin-binding Element Mediates Leukemia Inhibitory Factor and Corticotropin-releasing Hormone Transcriptional Synergy J. Biol. Chem., April 18, 1997; 272(16): 10551 - 10557. [Abstract] [Full Text] [PDF]

				D. Ray and S. Melmed Pituitary Cytokine and Growth Factor Expression and Action Endocr. Rev., April 1, 1997; 18(2): 206 - 228. [Abstract] [Full Text]

				J.-M. Aubry, A. V. Turnbull, G. Pozzoli, C. Rivier, and W. Vale Endotoxin Decreases Corticotropin-Releasing Factor Receptor 1 Messenger Ribonucleic Acid Levels in the Rat Pituitary Endocrinology, April 1, 1997; 138(4): 1621 - 1626. [Abstract] [Full Text] [PDF]

				P. Navarra, U. Grohmann, G. Nocentini, G. Tringali, P. Puccetti, C. Riccardi, and P. Preziosi Hydroxyurea Induces the Gene Expression and Synthesis of Proinflammatory Cytokines In Vivo J. Pharmacol. Exp. Ther., January 1, 1997; 280(1): 477 - 482. [Abstract] [Full Text]

				G. P. Chrousos The Hypothalamic-Pituitary-Adrenal Axis and Immune-Mediated Inflammation N. Engl. J. Med., May 18, 1995; 332(20): 1351 - 1363. [Full Text] [PDF]