STAT3-mediated signaling dysregulates lung fibroblast-myofibroblast activation and differentiation in UIP/IPF.
STAT3 is a latent transcription factor that plays a role in regulating fibroblast function in fibrotic lung diseases. To further understand the role of STAT3 in the phenotypic divergence and function of human lung fibroblasts (LFs), we investigated the effect of basal and cytokine-induced STAT3 activity on indices of LF differentiation and activation, including expression of α-smooth muscle actin (α-SMA), collagen, and adhesion molecules Thy-1/CD90 and α(v) β(3) and β(5) integrins. We identified a population of fibroblasts from usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) lungs characterized by constitutively phosphorylated STAT3, lower proliferation rates, and diminished expression of α-SMA, Thy-1/CD90, and β(3) integrins compared with control LFs. Staining of UIP lung biopsy specimens demonstrated that phosphorylated STAT3 was not present in α-SMA-positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense fibrosis. STAT3 activation in LFs did not significantly influence basal or transforming growth factor β(1)-induced collagen I expression but inhibited expression of α-SMA, Thy-1/CD90, and αv β(3) integrins. Suppression of STAT3 signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor β(1) but increased basal α-SMA and restored β(3) integrin expression in LFs via an ALK-5-dependent, SMAD3/7-independent mechanism. These data suggest that STAT3 activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant STAT3 signaling plays a critical role in UIP/IPF pathogenesis.
UBC James Hogg Research Centre, Institute for Heart + Lung Health, St. Paul's Hospital, Vancouver, British Columbia, Canada. petchkov@mail.ubc.ca
Dmitri V
DV
Pechkovsky
Cecilia M
CM
Prêle
John
J
Wong
Cory M
CM
Hogaboam
Robin J
RJ
McAnulty
Geoffrey J
GJ
Laurent
Samuel S-M
SS
Zhang
Moisés
M
Selman
Steven E
SE
Mutsaers
Darryl A
DA
Knight
D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000473:pathology* / Q000503:physiopathology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D053683:Oncostatin M / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D018800:Thy-1 Antigens / Q000378:metabolism; D014161:Transduction, Genetic; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D000199:Actins; D024042:Collagen Type I; D039302:Integrin alphaVbeta3; D015850:Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018800:Thy-1 Antigens; D053773:Transforming Growth Factor beta1; D053683:Oncostatin M; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human