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Infection and Immunity, November 2002, p. 6068-6074, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6068-6074.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice

Sofia Agelaki,1 Christos Tsatsanis,1* Achille Gravanis,2 and Andrew N. Margioris1*

Deparment of Clinical Chemistry-Biochemistry,1 Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete, Greece2

Received 19 April 2002/ Returned for modification 29 May 2002/ Accepted 5 August 2002

Corticotropin-releasing hormone (CRH) exerts an anti-inflammatory effect indirectly, via cortisole production, and a proinflammatory effect directly on immune cells. The aim of the present work was to examine the effect of CRH on macrophage-derived cytokines both in vitro and in vivo. For the in vitro experiments we used two types of macrophages: (i) the RAW264.7 monocyte/macrophage cell line and (ii) thioglycolate-elicited peritoneal macrophages from BALB/c mice. We have found that CRH enhanced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-{alpha}), interleukin-1ß (IL-1ß), and IL-6 production. For the in vivo experiments we have used the LPS-induced endotoxin shock model in BALB/c mice, an established model for systemic inflammation in which macrophages are the major source of the proinflammatory cytokines responsible for the development of the shock. Administration of antalarmin, a synthetic CRH receptor 1 (CRHR1) antagonist, prior to LPS prolonged survival in a statistically significant manner. The effect was more evident at the early stages of endotoxin shock. CRHR1 blockade suppressed LPS-induced elevation of the macrophage-derived cytokines TNF-{alpha}, IL-1ß, and IL-6, confirming the role of CRH signals in cytokine expression. In conclusion, our data suggest that CRH signals play an early and crucial role in augmenting LPS-induced proinflammatory cytokine production by macrophages. Our data suggest that the diffuse neuroendocrine system via CRH directly affects the immune system at the level of macrophage activation and cytokine production.

* Corresponding author. Mailing address: University of Crete, School of Medicine, P.O. Box 1393, Heraklion 71409, Crete, Greece. Phone: 30-810-394833. Fax: 30-810-394581. E-mail for C. Tsatsanis: tsatsani{at}med.uoc.gr. E-mail for A. N. Margioris: andym{at}med.uoc.gr.

Editor: J. D. Clements

Infection and Immunity, November 2002, p. 6068-6074, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6068-6074.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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