Elsevier

Journal of Neuroimmunology

Volume 72, Issue 2, February 1997, Pages 131-136
Journal of Neuroimmunology

CRH and the immune system

https://doi.org/10.1016/S0165-5728(96)00178-6Get rights and content

Abstract

Inflammatory cytokines released during immune system activation can stimulate the hypothalamic–pituitary–adrenal axis and cause increased secretion of corticotropin-releasing hormone (CRH), adrenocorticotropin and glucocorticoids. Identification of CRH peptide and mRNA, as well as its receptors in immune tissues, suggested a role for this peptide as a mediator of the neuroendocrine–immune interactions. Experimental evidence suggests that CRH may modulate the immune and inflammatory responses via two pathways: an antiinflammatory one operated by centrally released CRH, most likely through stimulation of glucocorticoid and catecholamine release, and one proinflammatory, through direct action of peripherally released CRH. This review highlights these concepts. In addition preliminary data on immune activation and inflammatory response in CRH-deficient mice created in our laboratory are discussed.

Introduction

Communication between the nervous, endocrine and immune systems is achieved via ligands and receptors shared by all three systems (Payan and Goetzl, 1985; Bateman et al., 1989; Blalock, 1989; Saphier, 1989; Reichlin, 1993; Gaillard, 1994). The array of adaptative mechanisms elicited in response to threatened homeostasis constitutes the stress response. Immune activation together with the inflammatory process are elements of this adaptative response to stressors, which includes activation of the hypothalamic–pituitary–adrenal (HPA) axis (Chrousos and Gold, 1992). The HPA axis, via stimulation of hypothalamic release of corticotropin-releasing hormone (CRH) (Vale et al., 1981) and activation of the catecholaminergic system, is a major mediator of the stress response (Chrousos and Gold, 1992; Valentino et al., 1993). Cytokines stimulate the HPA axis directly, causing increased secretion of CRH, adrenocorticotropin (ACTH) and glucocorticoids (Leme and Schapoval, 1975; Besedovsky et al., 1986; Bateman et al., 1989; Rivier et al., 1989a), and indirectly by augmenting the release of other HPA axis regulators, such as catecholamines and prostaglandins (Katsuura et al., 1988; Rivier et al., 1989b; Watanabe et al., 1990). The intriguing concept that excessive activation of the immune system is restrained by the HPA axis, and particularly by adrenal glucocorticoids, has been proposed (Munck et al., 1984; Kapcala et al., 1996). In this review we will focus on the role of CRH during the activation of the immune system as a potential mediator of neuroimmune–endocrine interactions.

Section snippets

Cytokines activate the HPA axis

Upon activation of the immune system, a cascade of cytokines, including TNFα, IL-1, and IL-6, are produced by leukocytes and accessory cells of the inflammatory response. A plethora of studies has shown that cytokines can stimulate the HPA axis (Reichlin, 1993) and cause release of adrenal glucocorticoids, which then downregulate the expression of several components of inflammation (Fauci et al., 1976; Boumpas et al., 1993). Thus, a feedback system operates between activated adrenals and the

CRH in immune cells

A role for CRH expressed in peripheral tissues during activation of the immune system was postulated by identification of the peptide and its mRNA in immune tissues. Thus, immunoreactive CRH and CRH mRNA have been identified in human peripheral blood cells (Stephanou et al., 1990) and peripheral lymphocytes (Ekman et al., 1993). Bioactive and immunoreactive CRH is present in rat thymus and spleen (Redei, 1992; Aird et al., 1993). CRH mRNA has been found in rat thymus (Redei, 1992), and in mouse

In vitro actions

Several in vitro studies suggest an immunomodulatory action of CRH on immune cells, although findings have been contradictory. CRH has been shown to stimulate B- (McGillis et al., 1989) and T-lymphocyte proliferation and expression of IL2 receptors (Singh, 1989), enhance both lysis mediated by NK cells (Leu and Singh, 1991) and chemotaxis (Genedani et al., 1992), and enhance leukocyte IL1 and IL2 (Singh and Leu, 1990), and IL6 secretion (Leu and Singh, 1992). Other studies have shown CRH to

The CRH-deficient mouse: Immune and inflammatory responses

A CRH-deficient (CRH−/−) mouse has been created in our laboratory by targeted gene deletion and homologous recombination in embryonic stem cells (Muglia et al., 1994; Muglia et al., 1995). CRH−/− mice have low basal and stimulated corticosterone blood levels. Despite their altered glucocorticoid status, life expectancy of CRH−/− mice does not differ from their wild-type (CRH+/+) littermates and is not complicated by spontaneous infections or any other sign of immune system incompetence.

Summary

Although the regulation and function of CRH in various peripheral tissues are inadequately understood, experimental evidence strongly indicates that CRH is an important mediator of the communication between neuroimmune and endocrine systems during immune system activation. The effects of CRH on the inflammatory response are both stimulatory and inhibitory, and are likely exerted by peripheral and central CRH, respectively. CRH-deficient mice provide a unique model with which to study the role

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    Current address: Department of Pediatrics and Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA.

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