Oncostatin-M up-regulates VCAM-1 and synergizes with IL-4 in eotaxin expression: involvement of STAT6.
Oncostatin-M (OSM) is an IL-6/gp130 family member that can stimulate the eosinophil-selective CC chemokine eotaxin-1 in vitro and eosinophil accumulation in mouse lung in vivo. The adhesion molecule VCAM-1 and eotaxin have been implicated in extravasation and accumulation of eosinophils into tissue in animal models of asthma. In this study, we investigated the role of OSM in regulation of VCAM-1 expression, and STAT6 tyrosine 641 phosphorylation in murine fibroblasts. OSM induced VCAM-1 expression in C57BL/6 mouse lung fibroblasts (MLF) and NIH 3T3 fibroblasts at the protein and mRNA level in vitro. OSM also induced STAT6 Y641 phosphorylation in MLF and NIH 3T3 fibroblasts, an activity not observed with other IL-6/gp130 cytokine family members (IL-6, leukemia inhibitory factor, cardiotropin-1, and IL-11) nor in cells derived from STAT6(-/-) mice (STAT6(-/-) MLF). STAT6 was not essential for OSM-induced VCAM-1 or eotaxin-1 as assessed in STAT6(-/-) MLF. Combination of IL-4 and OSM synergistically enhanced eotaxin-1 expression in MLF. IL-4 induction and the IL-4/OSM synergistic induction of eotaxin-1 was abrogated in STAT6(-/-) MLF, however, regulation of IL-6 was similar in -/- or wild-type MLF. Induction of VCAM-1 by OSM was diminished by pharmacological inhibitors of PI3K (LY294002) but not inhibitors of ERK1/2 (PD98059) or p38 MAPK (SB203580). These data support the role of OSM in eosinophil accumulation into lung tissue through eotaxin-1 and VCAM-1 expression and the notion that OSM is able to induce unique signal transduction events through its receptor complex of OSMR beta-chain and gp130.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Dominik K
DK
Fritz
Christine
C
Kerr
Li
L
Tong
David
D
Smyth
Carl D
CD
Richards
D000818:Animals; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053683:Oncostatin M; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D015850:Interleukin-6; C508352:Osm protein, mouse; D050800:STAT6 Transcription Factor; D019010:Vascular Cell Adhesion Molecule-1; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases