Abstract
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.
Copyright 2002 Wiley-Liss, Inc.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Collagen Type I / drug effects
-
Collagen Type I / genetics
-
Collagen Type I / metabolism
-
Connective Tissue Growth Factor
-
Dactinomycin / pharmacology
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / pharmacology
-
Fibroblasts / cytology
-
Fibroblasts / drug effects
-
Fibroblasts / metabolism*
-
Fibronectins / drug effects
-
Fibronectins / genetics
-
Fibronectins / metabolism
-
Gene Expression Regulation / drug effects
-
Humans
-
Immediate-Early Proteins / drug effects
-
Immediate-Early Proteins / genetics*
-
Immediate-Early Proteins / metabolism
-
Insulin / pharmacology
-
Intercellular Signaling Peptides and Proteins / genetics*
-
Intercellular Signaling Peptides and Proteins / metabolism
-
Interleukin-4 / metabolism*
-
Interleukin-4 / pharmacology
-
Lung / cytology
-
Lung / embryology
-
Lung / metabolism*
-
MAP Kinase Kinase Kinase 1*
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Promoter Regions, Genetic
-
Protein Serine-Threonine Kinases / antagonists & inhibitors
-
Protein Serine-Threonine Kinases / metabolism
-
RNA, Messenger / metabolism
-
Transforming Growth Factor beta / metabolism*
-
Transforming Growth Factor beta / pharmacology
Substances
-
CCN2 protein, human
-
Collagen Type I
-
Enzyme Inhibitors
-
Fibronectins
-
Immediate-Early Proteins
-
Insulin
-
Intercellular Signaling Peptides and Proteins
-
Phosphoinositide-3 Kinase Inhibitors
-
RNA, Messenger
-
Transforming Growth Factor beta
-
Connective Tissue Growth Factor
-
Dactinomycin
-
Interleukin-4
-
Protein Serine-Threonine Kinases
-
MAP Kinase Kinase Kinase 1
-
MAP3K1 protein, human