title: Calcitonin gene-related peptide inhibits chemokine production by human dermal microvascular endothelial cells.
abstract: This study examined whether the sensory neuropeptide calcitonin gene-related peptide (CGRP) inhibits release of chemokines by dermal microvascular endothelial cells. Dermal blood vessels are associated with nerves containing CGRP, suggesting that CGRP-containing nerves may regulate cutaneous inflammation through effects on vessels. We examined CGRP effects on stimulated chemokine production by a human dermal microvascular endothelial cell line (HMEC-1) and primary human dermal microvascular endothelial cells (pHDMECs). HMEC-1 cells and pHDMECs expressed mRNA for components of the CGRP and adrenomedullin receptors and CGRP inhibited LPS-induced production of the chemokines CXCL8, CCL2, and CXCL1 by both HMEC-1 cells and pHDMECs. The receptor activity-modifying protein (RAMP)1/calcitonin receptor-like receptor (CL)-specific antagonists CGRP₈-₃₇ and BIBN4096BS, blocked this effect of CGRP in a dose-dependent manner. CGRP prevented LPS-induced IκBα degradation and NF-κB binding to the promoters of CXCL1, CXCL8 and CCL2 in HMEC-1 cells and Bay 11-7085, an inhibitor of NF-κB activation, suppressed LPS-induced production of CXCL1, CXCL8 and CCL2. Thus, the NF-κB pathway appears to be involved in CGRP-mediated suppression of chemokine production. Accordingly, CGRP treatment of LPS-stimulated HMEC-1 cells inhibited their ability to chemoattract human neutrophils and mononuclear cells. Elucidation of this pathway may suggest new avenues for therapeutic manipulation of cutaneous inflammation.
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Lori L
authors.initials: LL
authors.lastname: Stohl
authors.forename: Xi
authors.initials: X
authors.lastname: Zhou
authors.forename: Wanhong
authors.initials: W
authors.lastname: Ding
authors.forename: Richard D
authors.initials: RD
authors.lastname: Granstein
mesh_terms: D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002460:Cell Line; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000502:physiology; D010446:Peptide Fragments; D012333:RNA, Messenger / Q000032:analysis; D058261:Receptor Activity-Modifying Proteins / Q000378:metabolism*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000098:blood supply
chemical_list: D019743:Chemokines, CXC; D010446:Peptide Fragments; D012333:RNA, Messenger; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide