Interleukin-4 regulates connective tissue growth factor expression in human lung fibroblasts.
Transforming growth factor-beta (TGF-beta) and interleukin-4 (IL-4) have fibrogenic properties and induce extracellular matrix production in a variety of lung diseases. Connective tissue growth factor (CTGF) is a matrix signaling molecule stimulated by TGF-beta that in part mediates alpha1(I) collagen mRNA expression. In these studies, the regulation of CTGF expression by IL-4 in human lung fibroblasts was examined. Following 6 h of stimulation with IL-4, basal CTGF mRNA levels were unchanged as assessed by Northern blot analysis. However, IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA expression by 50%. This effect was selective because IL-4 did not affect fibronectin or alpha1(I) collagen mRNA expression induced by TGF-beta. Experiments employing the transcriptional inhibitor actinomycin D suggest that IL-4 did not affect the stability of the CTGF mRNA. Transient transfection assays with 3TP-Lux, a luciferase gene controlled by a TGF-beta inducible promoter, and with a CTGF promoter construct indicate that IL-4 interfered with the TGF-beta-induced transcriptional activation of the CTGF gene.
Rishikof
David C
DC
The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA. drishikof@lung.bumc.bu.edu
Ricupero
Dennis A
DA
Kuang
Ping-Ping
PP
Liu
Hanqiao
H
Goldstein
Ronald H
RH
D024042:Collagen Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D003609:Dactinomycin; D004791:Enzyme Inhibitors; D005353:Fibronectins; D017874:Immediate-Early Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C526317:CCN2 protein, human; C482576:MAP3K1 protein, human