Oncostatin M causes eotaxin-1 release from airway smooth muscle: Synergy with IL-4 and IL-13

Faffe, Débora S.; Flynt, Lesley; Mellema, Matthew S.; Moore, Paul; Silverman, Eric S.; Subramaniam, Venkat; Jones, Matthew R.; Mizgerd, Joseph P.; Whitehead, Timothy R.; Imrich, Amy; Panettieri, Reynold A.; Shore, Stephanie A.

doi:10.1016/j.jaci.2004.11.033

Cited by 48 publications

(51 citation statements)

References 48 publications

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“…Although STAT6-mediated transcriptional activity without phosphorylation may happen in ASM cells, as has been shown for STAT 1 in some cell lines, a ChIP assay clearly showed in vivo binding of STAT3, but not STAT6, to the CCL11 promoter following IL-17A stimulation. Furthermore, similar to our findings, STAT3-dependent CCL11 expression has been shown in oncostatin M-stimulated human ASM cells (35) and mouse fibroblasts (36). Taken together, our data showed for the first time the involvement of IL-17A-mediated gene expression via a STAT3-dependent pathway.…”

Section: Discussionsupporting

confidence: 91%

Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells

Saleh¹,

Shan²,

Halayko

et al. 2009

The Journal of Immunology

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IL-17A has been shown to be expressed at higher levels in respiratory secretions from asthmatics and to correlate with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanism remains unknown. We previously demonstrated that IL-17A mediates CC chemokine (CCL11) production from human airway smooth muscle (ASM) cells. In this study, we demonstrate that STAT3 activation is critical in IL-17A-mediated CCL11 expression in ASM cells. IL-17A mediated a rapid phosphorylation of STAT3 but not STAT6 or STAT5 in ASM cells. Interestingly, transient transfection with wild-type or mutated CCL11 promoter constructs showed that IL-17A-mediated CCL11 expression relies on the STAT6 binding site. However, STAT3 but not STAT6 in vivo binding to the CCL11 promoter was detected following IL-17A stimulation of ASM cells. Overexpression of DN STAT3 (STAT3β) abolishes IL-17A-induced CCL11 promoter activity. This effect was not observed with STAT6 DN or the STAT3 mutant at Ser727. Interestingly, disruption of STAT3 activity with the SH2 domain binding peptide, but not with control peptide, results in a significant reduction of IL-17A-mediated STAT3 phosphorylation and CCL11 promoter activity. IL-17A-mediated CCL11 promoter activity and mRNA were significantly diminished in STAT3- but not STAT6-silenced ASM cells. Finally, IL-17A-induced STAT3 phosphorylation was sensitive to pharmacological inhibitors of JAK2 and ERK1/2. Taken together, our data provide the first evidence of IL-17A-mediated gene expression via STAT3 in ASM cells. Collectively, our results raise the possibility that the IL-17A/STAT3 signaling pathway may play a crucial role in airway inflammatory responses.

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Section: Discussionsupporting

confidence: 91%

Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells

Saleh¹,

Shan²,

Halayko

et al. 2009

The Journal of Immunology

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“…Utilizing an adenoviral vector (Ad) overexpression system, we previously demonstrated that transient ectopic expression of mouse (m)OSM (AdmOSM) in the lungs of mice leads to ECM accumulation (13,14). AdmOSM also elicits a robust eosinophilic airway inflammation (14), which is consistent with OSM's ability to regulate eotaxin-1 expression in airway fibroblasts (14,15) and airway smooth muscle cells (16) in vitro. A recent study (6) has shown that administration of rmOSM to mouse lungs also induces similar effects as those of AdmOSM.…”

mentioning

confidence: 72%

“…STAT6 appears to regulate collagen synthesis (17) and has been implicated in fibrosis in an experimental model of scleroderma (18). In addition, OSM cooperates with IL-4 (15,16) and IL-13 (16) in promoting enhanced eotaxin-1 responses in a STAT6-dependent fashion (15). However, whether STAT6-mediated responses in vitro reflect responses to OSM in vivo is not known.…”

mentioning

confidence: 99%

“…IL-5 is important in eosinophil differentiation (48) and mobilization into the circulation from the bone marrow, whereas eotaxins establish a chemotactic gradient at local tissue sites for eosinophil recruitment (49). Because eotaxins are regulated by IL-4 and IL-13 in a STAT6-dependent fashion in various airway structural cells (15,16,50,51), this provides a mechanism by which Th2 cytokines in concert with eotaxin chemokines promote local tissue eosinophilia during inflammatory disease states.…”

mentioning

confidence: 99%

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A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

Fritz

Kerr

Fattouh

et al. 2011

The Journal of Immunology

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Oncostatin M (OSM), a pleiotropic cytokine of the gp130 cytokine family, has been implicated in chronic allergic inflammatory and fibrotic disease states associated with tissue eosinophilia. Mouse (m)OSM induces airway eosinophilic inflammation and interstitial pulmonary fibrosis in vivo and regulates STAT6 activation in vitro. To determine the requirement of STAT6 in OSM-induced effects in vivo, we examined wild-type (WT) and STAT6-knockout (STAT6−/−) C57BL/6 mouse lung responses to transient ectopic overexpression of mOSM using an adenoviral vector (AdmOSM). Intratracheal AdmOSM elicited persistent eosinophilic lung inflammation that was abolished in STAT6−/− mice. AdmOSM also induced pronounced pulmonary remodeling characterized by goblet cell hyperplasia and parenchymal interstitial fibrosis. Goblet cell hyperplasia was STAT6 dependent; however, parenchymal interstitial fibrosis was not. OSM also induced airway hyperresponsiveness in WT mice that was abolished in STAT6−/− mice. OSM stimulated an inflammatory signature in the lungs of WT mice that demonstrated STAT6-dependent regulation of Th2 cytokines (IL-4, IL-13), chemokines (eotaxin-1/2, MCP-1, keratinocyte chemoattractant), and extracellular matrix modulators (tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-13), but STAT6-independent regulation of IL-4Rα, total lung collagen, collagen-1A1, -1A2 mRNA, and parenchymal collagen and α smooth muscle actin accumulation. Thus, overexpression of mOSM induces STAT6-dependent pulmonary eosinophilia, mucous/goblet cell hyperplasia, and airway hyperresponsiveness but STAT6-independent mechanisms of lung tissue extracellular matrix accumulation. These results also suggest that eosinophil or neutrophil accumulation in mouse lungs is not required for OSM-induced lung parenchymal collagen deposition and that OSM may have unique roles in the pathogenesis of allergic and fibrotic lung disease.

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“…STAT3 has been shown to be activated by a number of different growth factors (VEGF, PDGF, and EGF), cytokines (IL-6 and OSM), and chemokines (eotaxin) that are known to be present in the airways of asthmatics, and, thus, likely has pleiotropic functions in the regulation of airway inflammation and airway structural changes. Additionally, STAT3 has been shown to be required for the upregulation of growth factors and chemokines in ASM (11,12). While the MAPK and PI3K signaling pathways in mitogen-induced smooth muscle cell proliferation have been well characterized (31,35), the role of STAT3 was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1

Simeone-Penney¹,

Severgnini²,

Rozo³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Oncostatin M causes eotaxin-1 release from airway smooth muscle: Synergy with IL-4 and IL-13

Cited by 48 publications

References 48 publications

Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells

Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells

A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1

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