Regulation of human lung fibroblast alpha 1(I) procollagen gene expression by tumor necrosis factor alpha, interleukin-1 beta, and prostaglandin E2.
We investigated the participation of prostaglandin (PG) E2 in the regulation of the alpha 1(I) procollagen gene expression by tumor necrosis factor alpha (TNF alpha), and interleukin-1 beta (IL-1 beta) in normal adult human lung fibroblasts. TNF alpha (100 units/ml) and IL-1 beta (100 units/ml) stimulated the production of PGE2 and caused a dose-dependent inhibition of up to 54 and 66%, respectively, of the production of type I procollagen. Preincubation of cultures with indomethacin partially reversed the inhibition of procollagen production induced by the cytokines. Cytokine-stimulated endogenous fibroblast PG accounted for 35 and 68% of the inhibition induced by TNF alpha and IL-1 beta, respectively. Steady-state mRNA levels for alpha 1(I) procollagen paralleled the changes in collagen production. The transcription rate of the alpha 1(I) procollagen gene was reduced by 58% by TNF alpha and by 43% by IL-1 beta. Cytokine-stimulated endogenous PG production accounted for half of these effects. These results indicate that TNF alpha and IL-1 beta inhibit the expression of the alpha 1(I) procollagen gene in human lung fibroblasts at the transcriptional level by a PGE2-independent effect as well as through the effect of endogenous fibroblast PGE2 released under the stimulus of the cytokines.
Diaz
A
A
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Munoz
E
E
Johnston
R
R
Korn
J H
JH
Jimenez
S A
SA
D000328:Adult; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005944:Glucosamine / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008168:Lung; D008715:Methionine / Q000378:metabolism; D008875:Middle Aged; D011347:Procollagen / Q000235:genetics*; D014176:Protein Biosynthesis; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006023:Glycoproteins; D006025:Glycosaminoglycans; D007375:Interleukin-1; D011347:Procollagen; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D003094:Collagen; D008715:Methionine; D015232:Dinoprostone; D005944:Glucosamine; D007213:Indomethacin