Cytokines modulate cilomilast response in lung fibroblasts.
Fibroblasts, as a major source of extracellular interstitial connective tissue matrix, play an important role in wound healing and the development of fibrosis. The phosphodiesterase (PDE) 4 inhibitor cilomilast inhibits fibroblast chemotaxis and fibroblast-mediated gel contraction. Using the Boyden blindwell chamber chemotaxis assay and the type I collagen gel contraction model, this study investigated whether specific cytokines modulate cilomilast's inhibitory effect through regulation of endogenous PGE(2) production. Human recombinant IL-1beta stimulated PGE(2) production and shifted the cilomilast concentration-dependence curve to the left in both assay systems, indicating increased sensitivity to cilomilast. In contrast, human recombinant IL-4 inhibited PGE(2) production and shifted the cilomilast concentration-dependence curve to the right in both systems. In summary, the inhibitory effect of cilomilast on fibroblast migration and collagen gel contraction is modulated by IL-1beta and IL-4 through regulation of PGE(2) production.
Kohyama
Tadashi
T
Department of Respiratory Medicine, University of Tokyo, Tokyo, Japan.
Liu
Xiangde
X
Wen
Fu-Qiang
FQ
Kobayashi
Tetsu
T
Fang
Qiuhong
Q
Abe
Shinji
S
Cieslinski
Lenora
L
Barnette
Mary S
MS
Rennard
Stephen I
SI
D001993:Bronchodilator Agents / Q000494:pharmacology*; D002264:Carboxylic Acids; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000166:cytology; D009570:Nitriles; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism
D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D007375:Interleukin-1; D009570:Nitriles; D011994:Recombinant Proteins; D015847:Interleukin-4; C433247:Cilomilast; D003094:Collagen; D015232:Dinoprostone