Cytokine inhibition of fibroblast-induced gel contraction is mediated by PGE2 and NO acting through separate parallel pathways

Kui Zhu Yun Kui Zhu, X. D. Liu, M. C. Sköld, T. Umino, H. Wang, D. J. Romberger, J. R. Spurzem, T. Kohyama, F. Q. Wen, S. I. Rennard

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Contraction of three-dimensional collagen gels is a model of the contraction that characterizes normal healing and remodeling after injury. In the current study, we evaluated the hypothesis that a number of inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ, modulate this process by induction of prostaglandin (PG) E2 and nitric oxide (NO) production and that these secondary mediators function in an autocrine or paracrine manner to modulate contraction. Human fetal lung fibroblasts (HFL) were cultured in type I collagen gels and floated in medium containing TNF-α, IL-1β, or IFN-γ alone or in combination (cytomix). All cytokines inhibited the contraction significantly. The potency order was IL-1β, TNF-α, IFN-γ. The cytomix was no more potent than was IL-1β alone. PGE2 production was increased by TNF-α (5.0 versus 0.16 ng/ml, P < 0.01), IL-1β (5.3 versus 0.16 ng/ml, P < 0.01), and cytomix (5.9 versus 0.16 ng/ml, P < 0.01), and was completely inhibited by indomethacin. Indomethacin (P < 0.05) and L-NG-monomethyl arginine citrate (L-NMMA) (P < 0.05) alone both partially attenuated the inhibition of contraction caused by cytokines alone or by cytomix. Indomethacin and L-NMMA together attenuated inhibition more than either alone (P < 0.05). Exogenous PGE2 and exogenous NO donors (DETA nononate and 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride) inhibited the contraction significantly. The protein kinase A inhibitor KT5270 and the protein kinase G inhibitor Rp-pCPT-cGMPS attenuated the inhibition induced by PGE2 and NO, respectively. In summary, PGE2 and NO appear to function in parallel as autocrine/paracrine mediators of cytokine-driven fibroblast inhibition of the contraction of collagen gels and may contribute to remodeling during repair and inflammation in lung disorders.

Original languageEnglish (US)
Pages (from-to)245-253
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Issue number2
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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