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(American Journal of Pathology. 2003;163:345-354.)
© 2003 American Society for Investigative Pathology

Fibroblasts Isolated from Normal Lungs and Those with Idiopathic Pulmonary Fibrosis Differ in Interleukin-6/gp130-Mediated Cell Signaling and Proliferation

Yuben P. Moodley*{dagger}, Amelia K. Scaffidi*{dagger}, Neil L. Misso*{dagger}, Carmel Keerthisingam{ddagger}, Robin J. McAnulty{ddagger}, Geoff J. Laurent{ddagger}, Steven E. Mutsaers*{dagger}, Philip J. Thompson*{dagger} and Darryl A. Knight*{dagger}

From the Asthma and Allergy Research Institute,* Sir Charles Gairdner Hospital, Nedlands, Western Australia; the Department of Medicine,{dagger} University of Western Australia, Nedlands, Western Australia; and the Center for Cardiopulmonary Biochemistry and Respiratory Medicine,{ddagger} Royal Free and University College Medical School, University College London, London, United Kingdom

Interleukin (IL)-6 and IL-11 are elevated in a variety of lung conditions and may impact on repair mechanisms in chronic inflammatory disorders. However, the mechanisms by which these cytokines influence fibroblast proliferation in normal and disease states have not been previously addressed. We examined the effect of these cytokines on proliferation and cell-cycle kinetics of primary human lung fibroblasts obtained from normal patients and patients with idiopathic pulmonary fibrosis (IPF). IL-6 inhibited the proliferation of normal fibroblasts due to the sustained phosphorylation of STAT-3 and production of the cyclin-dependent kinase inhibitor p19INK4D. In contrast IL-6 was mitogenic for IPF fibroblasts due to the sustained activation of MAPK, which in turn inhibited the production of p27Kip1, allowing activation of cyclin D1 and hyperphosphorylation of retinoblastoma protein. IL-11 was mitogenic for both normal and IPF fibroblasts. These results provide strong evidence for a fundamental abnormality in a cytokine-signaling pathway, as opposed to alterations in cytokine production, in the pathogenesis of IPF.




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