Imatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro.
OBJECTIVE
Systemic sclerosis (SSc) is a heterogeneous multifactorial disease dominated by progressive skin and internal organ fibrosis that is driven in part by transforming growth factor-beta (TGF-β). An important downstream target of TGF-β is the Abelson (c-Abl) tyrosine kinase, and its inhibition by imatinib mesylate (Gleevec) attenuates fibrosis in mice. Here we examined the effect of c-Abl activation and blockade in explanted healthy control and SSc fibroblasts.


METHODS
Skin biopsies and explanted fibroblasts from healthy subjects and patients with SSc were studied. Changes in genome-wide expression patterns in imatinib-treated control and SSc fibroblasts were analysed by DNA microarray.


RESULTS
Treatment of control fibroblasts with TGF-β resulted in activation of c-Abl and stimulation of fibrotic gene expression that was prevented by imatinib. Moreover, imatinib reduced basal collagen gene expression in SSc but not control fibroblasts. No significant differences in tissue levels of c-Abl and phospho-c-Abl were detected between SSc and control skin biopsies. In vitro, imatinib induced dramatic changes in the expression of genes involved in fibrosis, cardiovascular disease, inflammation, and lipid and cholesterol metabolism. Remarkably, of the 587-imatinib-responsive genes, 91% showed significant change in SSc fibroblasts, but only 12% in control fibroblasts.


CONCLUSIONS
c-Abl plays a key role in fibrotic responses. Imatinib treatment results in dramatic changes in gene expression in SSc fibroblasts but has only modest effects in control fibroblasts. These data provide novel insights into the mechanisms underlying the antifibrotic effect of imatinib in SSc.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA. m-hinchcliff@northwestern.edu
Monique
M
Hinchcliff
Chiang-Ching
CC
Huang
Wataru
W
Ishida
Feng
F
Fang
Jungwha
J
Lee
Nadareh
N
Jafari
Mark
M
Wilkes
Swati
S
Bhattacharyya
Edward
E
Leof
John
J
Varga
D000818:Animals; D001549:Benzamides; D001706:Biopsy; D016022:Case-Control Studies; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D012595:Scleroderma, Systemic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053773:Transforming Growth Factor beta1; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl