Calcitonin Gene-Related Peptide Inhibits Proliferation and Antigen Presentation by Human Peripheral Blood Mononuclear Cells: Effects on B7, Interleukin 10, and Interleukin12

Abstract

CGRP is a neuropeptide that has previously been described to possess immunosuppressive activities. CGRP is released from peripheral nerves that, in the skin, are in close physical association with dendritic APC. We sought to investigate the mechanisms by which CGRP can inhibit immune responses by studying its effects on human peripheral blood mononuclear cells (PBMC). Using allogeneic monocytes as stimulator cells, CGRP could inhibit the proliferation of PBMC by 47% when CGRP was present for the duration of culture. Interestingly, when the stimulator monocytes were incubated with CGRP for 2 h prior to irradiation then washed, the observed inhibition increased to 85%, suggesting that CGRP was exerting a direct effect on the monocyte stimulator population. Finally, the recall response to tetanus toxoid (TT) by PBMC from individuals vaccinated with TT 14 d prior was inhibited by 25-50% in the presence of CGRP. Also, CGRP decreased the levels of B7.2 but not B7.1 on treated monocytes, and this inhibition could be abrogated by the addition of anti-IL-10 antibody, suggesting that the inhibition was mediated by an increase in IL-10 production. Moreover, increased IL-10 production was confirmed by ELISA. Both IL-12 p40 and IFN-gamma levels in CGRP-treated cultures were found to be decreased by approximately 30%. The decrease in IL-12 p40 levels could be reversed by addition of anti-IL-10. These data suggest that CGRP inhibits PBMC proliferation, in part, through the release of IL-10, which in turn can downregulate important co-stimulatory molecules and the cytokines IL-12 and IFN-gamma.

Calcitonin-gene related peptide (CGRP) inhibits interleukin-7-induced pre-B cell colony formation

“…CGRP reduces the rate of antigen presentation by Langerhans cells (LC) in mice [13,14]. A similar inhibition of antigen presentation was seen in human peripheral blood mononuclear cells, an event probably mediated by an increase in IL-10 [15,16]. The inhibition of LC function is likely responsible for the CGRP-induced down-regulation of contact and delayed-type hypersensitivity in mice.…”

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

“…Other studies support the potential suppression of delayed-type hypersensitivity as well as CH by CGRP (19). Finally, Fox et al (12) reported that treatment of human monocytes with CGRP for 2 h decreased their presentation of tetanus toxoid.…”

“…The neuropeptide treatment protocol was a modification of the one described by Fox et al (12). Immature DCs, after 7 days of culture with IL-4 (100 U/ml) and GM-CSF (1000 U/ml), were cultured with CGRP (10 Ϫ7 M) for 2 h at 37°C.…”

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.…”