Calcitonin gene-related peptide inhibits proliferation and antigen presentation by human peripheral blood mononuclear cells: effects on B7, interleukin 10, and interleukin 12.
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.
Fox
F E
FE
Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Kubin
M
M
Cassin
M
M
Niu
Z
Z
Hosoi
J
J
Torii
H
H
Granstein
R D
RD
Trinchieri
G
G
Rook
A H
AH
D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000502:physiology*; D051940:B7-2 Antigen; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D015740:Calcitonin Gene-Related Peptide