Calcitonin Gene-Related Peptide Decreases Expression of HLA-DR and CD86 by Human Dendritic Cells and Dampens Dendritic Cell-Driven T Cell-Proliferative Responses Via the Type I Calcitonin Gene-Related Peptide Receptor

Abstract

These studies were performed to establish whether functional receptors for calcitonin gene-related peptide (CGRP) are present on human dendritic cells (DCs) and to investigate potential immunomodulatory effects of CGRP on DCs other than Langerhans cells. Reverse transcriptase-PCR revealed expression of mRNA for a type 1 CGRP receptor by mature and immature blood-derived DCs. Sequence analysis confirmed the identity of the type 1 CGRP receptor (CGRP-R1). Addition of CGRP (10−7 M) to mature and immature DCs resulted in mobilization of intracellular calcium. Treatment of immature DCs with CGRP (10−7 M), before and after maturation in monocyte-conditioned medium, resulted in decreased cell surface expression of HLA-DR MHC class II and the costimulatory molecule, CD86. Treatment of immature DCs with CGRP (10−7 M) also resulted in decreased expression of CD86, but expression of HLA-DR was unchanged. When CGRP-treated mature DCs were used to stimulate allogeneic T cells, proliferative responses were dampened (∼50%), especially at low DC:T cell ratios (1:360). This effect was not observed with CGRP-treated, immature DCs. In contrast, CGRP-treated mature or immature DCs were no less efficient than untreated DCs in driving syngeneic T cell-proliferative responses to staphylococcal enterotoxin B. We conclude that mature and immature DCs express type 1 CGRP receptors and that signaling through these receptors may dampen mature DC-driven T cell proliferation most likely via down-regulation of CD86 and HLA-DR.

Endogenous NGF regulates CGRP expression in human monocytes, and affects HLA-DR and CD86 expression and IL-10 production

“…The main effect of CGRP administration both in vitro and in vivo is to dampen the immune response essentially by affecting antigen presentation in a variety of APCs such as Langerhans cells, dendritic cells, monocytes, and macrophages. 32,33,53,55,56 Our results on the functional effect of the autocrine synthesis of CGRP in monocytes indicate that the control of MHC class II and B7 costimulatory molecules is indeed a key feature of the biologic action of CGRP.As previously demonstrated, LPS stimulation strongly upregulates B7.1 (CD80) in adherent monocytes, 57 whereas B7.2 (CD86), which is constitutively expressed, is down-regulated by LPS 58,59 as well as HLA-DR. 48 In our study we show for the first time that the described LPS-induced reduction in CD86 and HLA-DR expression in human monocytes 48,58,60 is mediated by the LPS-induced synthesis of NGF and CGRP. Our data show that in LPS-activated monocytes, the neutralization of endogenous NGF, by reducing the synthesis of CGRP, up-regulates CD86 but does not modify CD80 expression.…”

“…Complementary to this observation are the findings showing that the administration of exogenous CGRP to monocyte-derived dendritic cells decreased HLA-DR expression and inhibited T-cell proliferative response. 56 Furthermore, in septic patients characterized by decreased MHC class II molecule expression in monocytes, 70,71 CGRP plasma levels are greatly enhanced and the highest levels are associated with a lethal outcome. 72 These findings, together with our in vitro data, suggest that CGRP could be a key mediator of the LPS-induced responses.…”

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

“…Here, ADM2 was demonstrated to inhibit MHCII expression in adipocytes primarily through CRLR/RAMP1, which is the classical pharmacological CGRP 1 receptor (45). In agreement with our present findings, some reports have shown that CGRP reduced MHCII expression in dendritic cells and hair follicle dermal papilla (46,47), although the exact mechanism remains unclear.…”

Calcitonin Gene-Related Peptide Is an Important Regulator of Cutaneous Immunity: Effect on Dendritic Cell and T Cell Functions

“…Further, to understand human skin diseases, it is important to consider the possibility that neurotransmitter concentration is controlled by a patient's mental condition and that an Ag can have a direct effect on the nervous system. In fact, CGRP treatment inhibits Ag presentation by human peripheral mononuclear cells and human DCs (47,48). Determination of the mechanisms underlying CGRP-mediated immune regulation will open up a new avenue for understanding various types of skin inflammation and skin diseases.…”