title: p38 Inhibition attenuates the pro-inflammatory response to C-reactive protein by human peripheral blood mononuclear cells.
abstract: An active role for C-reactive protein (CRP) in inflammatory vascular diseases has been recently suggested. Monocytes play an important role in vascular pathology and are activated by p38 mitogen activated protein kinase (MAPK) dependent mechanisms in many inflammatory settings. Therefore, we investigated whether CRP directly promotes a pro-inflammatory phenotype in human peripheral blood mononuclear cells (HPBMC) via p38 MAPK signaling. CRP exposure leads to a rapid phosphorylation of p38 MAPK in HPBMC. CRP-induced p38 kinase activity in HPBMC was blocked by treatment with an inhibitor of p38 kinase, SD-282. CRP-induced the expression of tissue factor protein and the secretion of IL-6, IL-8, IL-1beta, TNFalpha and PGE(2). Co-exposure to CRP and SD-282 blocked the secretion of these pro-inflammatory and pro-thrombotic mediators. CRP treatment elevated IL-6, IL-8, IL-1beta, TNFalpha, COX-2 and TF mRNA expression. These effects of CRP also required p38 activity, since SD-282 blocked mRNA induction of each. Taken together these data suggest a mechanistic relationship between p38 MAPK signaling and CRP-induced pro-inflammatory and pro-thrombotic activities in HPBMC. Thus, p38 inhibition may represent a novel approach to attenuate inflammation and its consequences in cardiovascular disease.
authors.affiliation: Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
authors.forename: Moon Y
authors.initials: MY
authors.lastname: Lim
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: Maile
authors.initials: M
authors.lastname: O'connell
authors.forename: Gilbert
authors.initials: G
authors.lastname: O'Young
authors.forename: Heather Ann
authors.initials: HA
authors.lastname: Brauer
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Luedtke
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: George S
authors.initials: GS
authors.lastname: Schreiner
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism*
chemical_list: D016708:Synaptophysin; D002097:C-Reactive Protein