Peripheral corticotropin-releasing hormone and urocortin in the control of the immune response
Introduction
As more sensitive techniques are being developed for the detection of peptides in plasma and tissue extracts, it is becoming increasingly clear that peptide hormones which were once believed to be solely of brain and pituitary origin are, in fact, involved in a large number of paracrine and autocrine actions with-in the periphery.
The hypothalamic peptide, corticotropin-releasing hormone (CRH), is responsible for triggering the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland during times of neurological stress [57], [82], [120] and is a classical example of a neuropeptide with multiple actions in almost every tissue of the body. After the initial characterization of CRH as an ACTH releasing peptide using perfused rat pituitary cell columns and its subsequent purification from ovine [120] and rat [83] hypothalami, basic radioimmunoassays were developed to detect CRH in a variety of tissues. Gel filtration, affinity and high performance liquid chromatographic techniques were used to confirm that immunoreactive (ir) CRH from peripheral tissues had similar elution patterns to both synthetic and purified hypothalamic CRH. As with many hypothalamic peptides, CRH-like ir was found to be present in large quantities in extracted human placenta [93], which explained the increasing concentrations of ir-CRH in the circulation during the progression of pregnancy [18], [87], [88]. CRH levels appeared much lower in other tissues, yet were significant in the spinal cord, lung, pancreas, gastrointestinal tract, and adrenal glands [74], [108]. The development of a specific CRH immunoradiometric assay [56], together with immunohistochemistry, in situ hybridization, northern blot and PCR techniques, confirmed the above findings, but also led to further discoveries regarding the extensive distribution of CRH.
Section snippets
Distribution of CRH in the immune system
CRH-like ir and mRNA were first detected in cells of the immune system in 1990 using in situ hybridization histochemistry, northern blot analysis and CRH radioimmunoassay (RIA) [107]. Separation of large numbers of lymphocytes by density gradient centrifugation and neutrophils by dextran sedimentation of the lymphocyte depleted blood, followed by peptide and mRNA analysis, led to the conclusion that CRH-ir and mRNA were present in both human peripheral blood lymphocytes and neutrophils, yet in
Upregulation of CRH expression in immune cells and tissues
In experiments where adjuvant-induced arthritic rats were used as models for chronic inflammatory stress, Jessop et al. demonstrated a slight increase in CRH-ir in the spleen and thymus 14 and 11 days respectively after initiation of the inflammatory response [41]. This work provided preliminary evidence for a link between inflammation and CRH release, yet the factor responsible for initiating this release was unknown. The production of cytokines such as IL-1, IL-6 and TNF-α by activated cells
Urocortin—the new ’immune’ CRH?
In 1995 a new mammalian member of the CRH family of genes was cloned from rat midbrain [124]. Translation of the DNA sequence revealed the peptide to share 44% amino acid homology with human and rat CRH, but interestingly, it had an even greater degree of identity with fish urotensin, a brain and spinal cord peptide possessing potent ACTH releasing activity [37], [53]. Like urotensin, urocortin was found to possess high affinity for the CRH binding protein [8] (found in the brain and
CRH receptors in the immune system
Experiments which revealed binding of [125I] CRH to spleen cells [28], peripheral sympathetic nerves [119], aortic endothelium [27] and monocytes and T-lymphocytes [96] provided the basis for further studies on the distribution and roles of CRH receptors in the immune system. Other groups later confirmed the presence of CRH binding sites in the spleen [125], and on monocytes [4], [98] and T-lymphocytes [4] demonstrating a functional coupling of these receptors to a G-protein and cAMP signaling
Effects of CRH and UCN on the immune system
There are several problems associated with observing the effects of peripherally administered CRH and UCN. Firstly, if the experiments are carried out in man, there may be some sequestering of peptide activity by the circulating CRH-binding protein [8], [76], however, if sufficient doses are given, ACTH releasing activity is observed, demonstrating that the unbound fraction of CRH or UCN in the blood does have the ability to reach its target tissues [90]. Even in experiments carried out in rats
Discussion
It seems likely that peripheral secretions of CRH and UCN are involved in the modulation of the peripheral immune response by acting at specific receptors on multiple populations of immunocytes to produce a wide range of effects (Fig. 1). The peptides are likely to be both of neural and immune cell origin, but do not appear to be released at particularly high concentrations. Different doses of peripherally administered CRH and UCN result in either an enhanced or reduced immune response, the
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