Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts.
Levels of pulmonary and activation-regulated chemokine (PARC) mRNA and protein are increased in the lungs of patients with pulmonary fibrosis. The purpose of this study was to establish whether PARC could be directly involved in development of pulmonary fibrosis by stimulating collagen production in lung fibroblasts. Exposure to PARC increased production of collagen mRNA and protein by 3- to 4-fold in normal adult lung and dermal fibroblast cells. Collagen mRNA transiently increased after 3-6 h of activation with PARC, with an increase in collagen protein detected after 24 h of activation. At the same time, PARC had less pronounced effect on fibroblast proliferation, not exceeding 50% increase over control nonstimulated cells. PARC intracellular signaling led to activation of ERK1/2, but not p38, in fibroblasts; pharmacologic inhibition of ERK, but not p38, also blocked PARC's effect on collagen production. Inhibition experiments with pertussis toxin suggested that PARC receptor is G protein-coupled. Thus, PARC is a member of the CC chemokine family that acts directly as a profibrotic factor.
Atamas
Sergei P
SP
Baltimore VA Medical Center, Research Service (151), Room 3C-125, 10 North Greene Street, Baltimore, MD 21201, USA. satamas@umaryland.edu
Luzina
Irina G
IG
Choi
Jung
J
Tsymbalyuk
Natalya
N
Carbonetti
Nicholas H
NH
Singh
Ishwar S
IS
Trojanowska
Maria
M
Jimenez
Sergio A
SA
White
Barbara
B
D002478:Cells, Cultured; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases
C111792:CCL18 protein, human; D019742:Chemokines, CC; D024042:Collagen Type I; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins