Regulation of corticotropin-releasing hormone receptor-2 expression in human cord blood-derived cultured mast cells

Abstract

Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal (HPA) axis; it is also secreted outside the brain where it exerts proinflammatory effects, possibly through mast cell activation. Mast cells are necessary for allergic reactions, but are increasingly implicated in acquired immunity and inflammatory diseases worsened by stress. Acute stress and intradermal CRH induced murine skin mast cell activation and increased vascular permeability that was absent in W/W v mast cell deficient mice. The presence of functional CRH receptors (CRH-R) was recently reported on human mast cells. Here, we studied the expression of CRH-R1 and CRH-R2 by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescent immunocytochemistry in human umbilical cord blood-derived cultured mast cells (hCBMCs) treated with Interleukin (IL)-1, IL-4 or lipopolysaccharide (LPS). Ten week-old hCBMCs cultured in the presence of Stem cell factor (SCF) and IL-6 were positive for both CRH-R1 and CRH-R2. However, the expression of only CRH-R2 mRNA and protein was induced by priming hCBMCs with IL-4 for the last three weeks of culture. Further analysis of the CR-H R2 mRNA expression showed that addition of IL-1 or LPS for 6 h increased only CRH-R2 gene expression. CRH had negligible effect on IL-6 secretion from non-primed hCBMCs, but induced release from IL-4 primed cells. Interestingly, LPS alone increased IL-6 release in non-primed cells, but lost this effect in primed cells. These results further implicate mast cells and CRH in either initiating or potentiating inflammatory diseases, especially those affected by stress. Journal of Molecular Endocrinology (2005) 35, R1-R8

Corticotropin Releasing Factor (CRF) Activation of NF-κB-Directed Transcription in Leukocytes

“…Venihaki et al (2003) found CRF-R2 mRNA expressed in splenocytes. There is also preliminary evidence for CRF-R2 expression in both the spleen and thymus (Baigent, 2001), as well as on mast cells (Papadopoulou et al, 2005). Thus, our studies do not rule out the possibility that, in other systems or cell types, that CRF-R2 can be immunomodulatory.…”

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

“…The presence of CRHR2 on resident and circulating immune cells such as granulocytes, monocytes, plasma, and mast cells (14,25,26) and its up-regulation on intestinal plasma cells and macrophages in patients with ulcerative colitis (22), along with the altered susceptibility of CRH-deficient mice to inflammatory (27)(28)(29) and autoimmune conditions (30), prompted us to examine intestinal inflammatory responses in CRHR2-null mice. For that purpose, we applied the C. difficile toxin A-mediated mouse model of acute intestinal inflammation, which has been previously used by us to demonstrate a peripheral proinflammatory role for CRH (29,31) mediated, at least in part, by CRHR1 (31).…”

Recognition Sites for Microbes and Components of the Immune System on Human Mast Cells: Relationship to CD Antigens and Implications for Host Defense

“…Thus, IL-4 promotes the expression of chymase as well as expression ofFcERI in developing (SCF-dependent) human MCs (32). In addition, IL-4 has been reported to upregulate expression of corticotropin-releasing hormone receptor-2 (CRHR-2) on human mast cells (33). MC stimulation by CRH could lead to secretion of proinflammatory mediators that recruit circulating immune cells to inflammation sites and activate local immune accessory cells as well as peripheral nerves.…”