Fibroblasts isolated from normal lungs and those with idiopathic pulmonary fibrosis differ in interleukin-6/gp130-mediated cell signaling and proliferation.
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 p19(INK4D). In contrast IL-6 was mitogenic for IPF fibroblasts due to the sustained activation of MAPK, which in turn inhibited the production of p27(Kip1), allowing activation of cyclin D(1) 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.
Moodley
Yuben P
YP
Asthma and Allergy Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Scaffidi
Amelia K
AK
Misso
Neil L
NL
Keerthisingam
Carmel
C
McAnulty
Robin J
RJ
Laurent
Geoff J
GJ
Mutsaers
Steven E
SE
Thompson
Philip J
PJ
Knight
Darryl A
DA
D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism; D016376:Oligonucleotides, Antisense; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000199:Actins; D015703:Antigens, CD; C493974:CDKN2D protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494199:IL6ST protein, human; D017370:Interleukin-11; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D008934:Mitogens; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D050822:Cytokine Receptor gp130; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases