Fibroblasts isolated from normal lungs and those with idiopathic pulmonary fibrosis differ in interleukin-6/gp130-mediated cell signaling and proliferation

Yuben P Moodley; Amelia K Scaffidi; Neil L Misso; Carmel Keerthisingam; Robin J McAnulty; Geoff J Laurent; Steven E Mutsaers; Philip J Thompson; Darryl A Knight

doi:10.1016/S0002-9440(10)63658-9

Fibroblasts isolated from normal lungs and those with idiopathic pulmonary fibrosis differ in interleukin-6/gp130-mediated cell signaling and proliferation

Am J Pathol. 2003 Jul;163(1):345-54. doi: 10.1016/S0002-9440(10)63658-9.

Authors

Yuben P Moodley¹, Amelia K Scaffidi, Neil L Misso, Carmel Keerthisingam, Robin J McAnulty, Geoff J Laurent, Steven E Mutsaers, Philip J Thompson, Darryl A Knight

Affiliation

¹ Asthma and Allergy Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Antigens, CD / metabolism*
Cell Cycle Proteins / metabolism
Cell Division / physiology*
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p19
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors
Cytokine Receptor gp130
DNA-Binding Proteins / metabolism
Enzyme Activation
Enzyme Inhibitors / metabolism
Fibroblasts / cytology
Fibroblasts / physiology*
Humans
Interleukin-11 / metabolism*
Interleukin-6 / metabolism*
Lung / cytology
Lung / metabolism*
Lung / pathology
Membrane Glycoproteins / metabolism*
Mitogen-Activated Protein Kinases / metabolism
Mitogens / metabolism
Oligonucleotides, Antisense
Pulmonary Fibrosis / metabolism*
Pulmonary Fibrosis / pathology
STAT3 Transcription Factor
Signal Transduction / physiology*
Trans-Activators / metabolism
Tumor Suppressor Proteins / metabolism

Substances

Actins
Antigens, CD
CDKN2D protein, human
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p19
DNA-Binding Proteins
Enzyme Inhibitors
IL6ST protein, human
Interleukin-11
Interleukin-6
Membrane Glycoproteins
Mitogens
Oligonucleotides, Antisense
STAT3 Transcription Factor
STAT3 protein, human
Trans-Activators
Tumor Suppressor Proteins
Cytokine Receptor gp130
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases
Mitogen-Activated Protein Kinases