title: Calcitonin gene-related peptide mediates an inflammatory response in Schwann cells via cAMP-dependent ERK signaling cascade.
abstract: OBJECTIVE
  Calcitonin gene-related peptides (CGRP), an endogenous neuropeptide, play an important role in the development of neuroinflammation by acting upon its receptor. The CGRP receptor immunoreactivity was identified on Schwann cells. However the effects of CGRP on Schwann cells are unknown and the exact signaling mechanisms associated with CGRP receptor activation related to Schwann cells inflammatory responses are not well understood. We investigated the effect of CGRP on CGRP receptor activation mediates a proinflammatory signaling response in Schwann cells.
  
  
  METHODS
  CGRP-induced ERK-MAPK phosphorylation and proinflammatory cytokines, interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) expressions were measured by immune blotting. We also used specific antagonist and inhibitors to confirm the exactly signaling pathway including CGRP (8-37), SQ 22536 and H-89.
  
  
  RESULTS
  Treatment with CGRP demonstrated a significant generation of IL-1β and IL-6 but not in the level of TNF-α. In addition, there was a temporal increase in the activated form of ERK caused by CGRP that was prevented after pretreatment with CGRP (8-37), SQ 22536 and H-89. Furthermore, use of the CGRP (8-37), ERK inhibitor PD 98059, SQ 22536 or H-89 abolished the CGRP mediated increase in IL-1β.
  
  
  CONCLUSIONS
  This investigation provides evidence for a novel CGRP activation on Schwann cells that mediates inflammatory response by increasing of IL-1β and IL-6 expression. CGRP activates the cAMP-PKA-ERK signaling cascade leading to IL-1β production. These results support the notion that CGRP may play a direct role to initiate inflammatory processes in the peripheral nervous system.
authors.affiliation: Occupational Therapy Division, Faculty of Physical Therapy, Mahidol University, Nakornpathom 73170, Thailand.
authors.forename: Kannika
authors.initials: K
authors.lastname: Permpoonputtana
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Porter
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand; Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand. Electronic address: piyarat.gov@mahidol.ac.th.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D007546:Isoquinolines; D010455:Peptides; D018015:Receptors, Calcitonin Gene-Related Peptide; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D000225:Adenine; D015740:Calcitonin Gene-Related Peptide; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Calcitonin gene-related peptide; Interleukin-1β; Mitogen-activated protein kinases; Proinflammatory; Schwann cell