Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro.
BACKGROUND
Asthma is characterized by chronic inflammation of the airway with the presence of Th2 cytokines. Airway remodeling in asthma is closely related to clinical manifestations. Lung myofibroblasts play a critical role in the airway remodeling and Th2 cytokines may modulate their behavior. We examined the effect of two major Th2 cytokines, IL-4 and IL-13, on differentiation of lung fibroblasts to myofibroblasts. We hypothesized that these cytokines would stimulate fibroblast proliferation in association with decreased prostaglandin E(2) (PGE(2)).


METHODS
Lung fibroblasts were incubated with IL-4 and IL-13 with or without Th1 cytokine interferon-gamma (IFN-gamma) in vitro. Differentiation of lung fibroblasts to myofibroblasts was characterized by the expression of alpha-smooth muscle actin (alpha-SMA) as well as a morphological and immunohistochemical analysis. Fibroblast proliferation stimulated by IL-4 and IL-13 was assessed with the MTT assay. We also investigated the effect of these cytokines on cyclooxygenase (COX) gene expression and PGE(2) production.


RESULTS
IL-4 and IL-13 increased alpha-SMA expression and myofibroblastic differentiation. This effect was attenuated by IFN-gamma and dexamethasone failed to have an influence on differentiation. IL-4 and IL-13 stimulated fibroblast proliferation. These cytokines downregulated the expression of both COX-1 and COX-2 genes and decreased the production of PGE(2).


CONCLUSIONS
IL-4 and IL-13 induce differentiation of fibroblasts to myofibroblasts and this response is attenuated by IFN-gamma. IL-4 and IL-13 stimulate fibroblast proliferation and this effect is at least partly due to suppressed COX gene expressions and subsequently decreased PGE(2) production. These findings suggest that IL-4 and IL-13 directly act on lung fibroblast to induce a fibrogenic response.
Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. asaitou-tky@umin.ac.jp
Akira
A
Saito
Hitoshi
H
Okazaki
Isamu
I
Sugawara
Kazuhiko
K
Yamamoto
Hajime
H
Takizawa
D000199:Actins / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005355:Fibrosis / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D018793:Interleukin-13 / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000199:Actins; D018793:Interleukin-13; D007527:Isoenzymes; D008565:Membrane Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D012313:RNA; D007371:Interferon-gamma; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin