Pediatric Endocrinology Section, Developmental Endicrinology Branch, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892 USA
Cortic otropin-releasing hormone (CRH) is a major regulator
of the hypothalamic-pituitary-adrenal axis (HPA) and principal
coordinator of the stress response. As in stress, intracerebroventricular
administration of CRH suppresses the immune system indirectly,
via glucocorticoid and/or sympathetic system-mediated mechanisms.
Also, during inflammatory stress, the cytokines TNF
, IL-1, and
IL-6 stimulate hypothalamic CRH and/or vasopressin secretion
as a way of preventing the inflammatory reaction from overreacting.
Recently, CRH receptors were described in peripheral sites of
the immune system, and CRH was found to promote several immune
functions
in vitro. We demonstrated a direct role of CRH in
the inflammatory immune process
in vivo, by first studying the
effect of systemic CRH immunoneutralization in an experimental
model of carrageenin-induced aseptic inflammation in Spague-Dawley
rats. We extended these observations to other forms of experimental
inflammation, including streptococcal cell wall polysaccharide-
and adjuvant-induced arthritides and peptide R16 (epitope of
the interphotoreceptor retinoid-binding protein)-induced uveitis
in Lewis rats. We also studied human disease states, including
rheumatoid arthritis, Hashimoto thyroiditis, and ulcerative
colitis. Inflamed tissues contained large amounts of IR CRH,
reaching levels similar to those observed in the hypophyseal
portal system. We also demonstrated the presence of CRH mRNA
and CRH receptors in inflammatory cells and identified the mast
cells as a major immune target for CRH. In addition to production
by immune cells, the peripheral nervous system, including the
postganglionic sympathetic neurons and the sensory fibers type
C, appears to contribute to IR CRH production in inflammatory
sites. The production of CRH from the post-ganglionic sympathetic
neurons may be responsible for the stress-induced activation
of allergic/autoimmune phenomena, such as asthma and eczema,
via mast cell degranulation. Antalarmin, a novel nonpeptide
CRH receptor antagonist, displaced
125I-labeled ovine CRH binding
in rat pituitary, frontal cortex, and cerebellum, but not heart,
consistent with antagonism at the CRHR1 receptor.
In vivo antalarmin
significantly inhibited CRH-stimulated ACTH release and carrageenin-induced
subcutaneous inflammation in rats. Thus, antalarmin and other
related compounds that antagonize CRH at the level of its own
receptor have therapeutic potential in some forms of inflammation
directly mediated by type 1 CRH receptors and promise to enhance
our understanding of the many roles of CRH in immune/inflammatory
reactions.
