Corticotropin releasing hormone and the immune/inflammatory response

Abstract

Hypothalamic corticotropin-releasing hormone (CRH) acts as the major physiologic ACTH secretagog. Moreover, CRH is distributed in the brain and spinal cord, adrenal medulla, testes, ovaries, gastrointestinal tract, pancreas, myometrium, endometrium, placenta, and diverse inflammatory sites. Immunoreactive CRH has been found in the cytoplasm of immune accessory cells (macrophages, endothelial cells, and tissue fibroblasts), and in inflammatory sites of both acute and chronic inflammation (synovial lining cell layers and blood vessels from the joints of patients with rheumatoid arthritis and osteoarthritis). Additionally, the local presence of CRH in the uveitic eyes, cytoplasm of inflammatory cells (macrophages, lymphocytes, and polymorphonuclear cells) infiltrating the iris, ciliary body, vitreous, retina, and choroid appears to be of pivotal importance in the process of experimental autoimmune uveoretinitis. Traditionally, hypothalamic CRH has been considered to act indirectly in an anti-inflammatory fashion, since the end product of the hypothalamic-pituitaryadrenal axis is cortisol, a well-known anti-inflammatory compound. However, CRH produced at peripheral inflammatory sites has been shown to participate in an autocrine/paracrine stimulation of inflammation. Thus, CRH may have a peripheral, primarily activating role on the immune system. The mechanisms of the CRH-mediated component of the immune/inflammatory response are still unclear. CRH in inflammatory sites seems to be involved in the activation of the Fas/Fas ligand system. Furthermore, locally produced embryonic and endometrial CRH plays a role in both the aseptic inflammatory process of implantation and the anti-rejection process that protects the fetus from the maternal immune system. There are two types of G-protein-coupled CRH receptors (CRH-R1 and CRH-R2). Pyrrolopyrimidine compounds, such as antalarmin, have been developed as CRH-R1 receptor antagonists. Confirming the peripheral pro-inflammatory actions of CRH, antalarmin has been shown to suppress experimental aseptic inflammation. Thus, antalarmin may represent the first in a new class of anti-inflammatory agents operating through CRH-R1. Studies of CRH genetics have provided new insights on the pathogenesis of rheumatoid arthritis in humans. DNA variation across the CRH genecontaining region has been examined in families with multiple cases of rheumatoid arthritis. Transmission Disequilibrium Test analysis showed significant association at the CRH locus.European Journal of Endocrinology 155 S77-S84

Hypothalamic neurohormones and immune responses

“…These cells cooperate using molecular signals, including ILs, colony-stimulating factors, TNF, IFNs, transforming growth factor, and chemokines, vasoactive amines (histamine and serotonine), plasma proteases (kinine and complement systems), arachidonic acid metabolites (prostaglandins, leukotrienes, and lipoxins), platelet-activating factor, nitric oxide, and neuropeptides (Mastorakos et al, 2006). …”

On the function of placental corticotropin‐releasing hormone: a role in maternal‐fetal conflicts over blood glucose concentrations

“…Research generally demonstrates that circulating CRH stimulates monocyte production of pro‐inflammatory cytokines (e.g. Mastorakos, Karoutsou & Mizamtsidi, 2006), though inflammatory effects may depend on the receptor type [CRH‐R1 (pro‐inflammatory) versus CRH‐R2 (anti‐inflammatory)] and thereby the tissue (Zhu, Wang & Li, 2011). One way that placental CRH may function to increase maternal blood glucose levels, then, is via inflammatory signaling.…”

Activation of Adrenal Steroidogenesis and an Improvement of Mood Balance in Postmenopausal Females after Spa Treatment Based on Physical Activity

“…In these diseases, the CRH operates on both peripheral and central levels [4,5]. The CRH indirectly operates in an anti-inflammatory fashion via the stimulation of anti-inflammatory cortisol and immunoprotective adrenal androgens [6], while the autocrine/paracrine peripheral effect is the opposite [7].…”