A Role for T Helper 2 Cells in Mediating Skin Fibrosis in Tight-Skin Mice

Ong, Christopher J.; Ip, Simon; Teh, Soo-Jeet; Wong, Connie Hoi Yee; Jirik, Frank R.; Grusby, Michael J.; Teh, Hung‐Sia

doi:10.1006/cimm.1999.1537

Cited by 77 publications

(71 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both are profibrotic; IL-4 can induce collagen production in vivo and in vitro. In the skin-tight mouse model of scleroderma, the absence of IL-4 or Stat6 completely blocked the fibrosis seen in this model (41). In fact, a recent rodent study by Daley and colleagues (30) demonstrated Th2-mediated vascular remodeling, and the presence of HIMF in the inflammatory cells of these same remodeling vessels.…”

Section: Discussionmentioning

confidence: 87%

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Angelini¹,

Su²,

Yamaji-Kegan³

et al. 2009

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-b, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-b is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblastlike cells. We also show that addition of recombinant RELM-b induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-b may be involved in the development of scleroderma-associated pulmonary hypertension.

show abstract

Section: Discussionmentioning

confidence: 87%

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Angelini¹,

Su²,

Yamaji-Kegan³

et al. 2009

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…ECM accumulation in subepithelium compartments of smaller airways is possible (our own observations), however technically difficult to quantify, and higher or longer OSM expression may induce more pronounced effects on the major airways. Because OSM activates STAT6 (15) and because this signaling/transcription factor has been associated with the development of tissue fibrosis in some in vivo model systems (18), we hypothesized that OSM may regulate parenchymal ECM deposition through this pathway. Our results show that STAT6 is not required for the mOSM-induced parenchymal collagen or aSMA deposition that indicates myofibroblast hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

“…Among the gp130 cytokine family members, our studies implicate OSM as a unique inducer of signaling/transcription factor STAT6 activation in mouse lung fibroblasts (15). 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).…”

mentioning

confidence: 84%

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

View full text Add to dashboard Cite

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.

show abstract

“…In the TSK mouse, Th2 T cells infiltrate skin lesions and produce IL-4 (151). In this animal model, fibrosis can be prevented by null mutation of the IL-4 gene (151), by anti-IL-4 treatment (152), or by introduction of an IL-12-encoding plasmid (153).…”

Section: T Cells In Animal Models Of Sscmentioning

confidence: 99%