| First Author | Yamaji-Kegan K | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 9 | Pages | 5539-48 |
| PubMed ID | 20889544 | Mgi Jnum | J:165183 |
| Mgi Id | MGI:4836420 | Doi | 10.4049/jimmunol.0904021 |
| Citation | Yamaji-Kegan K, et al. (2010) Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMalpha) increases lung inflammation and activates pulmonary microvascular endothelial cells via an IL-4-dependent mechanism. J Immunol 185(9):5539-48 |
| abstractText | Hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 and resistin-like molecule alpha, belongs to a novel class of cysteine-rich secreted proteins. It exhibits mitogenic and chemotactic properties during pulmonary hypertension-associated vascular remodeling, as well as fibrogenic properties during pulmonary fibrosis. HIMF expression in the lung was reported to be regulated by Th2 cytokines (IL-4 and IL-13) via the transcription factor STAT6 pathway in a bleomycin-induced pulmonary fibrosis model. However, in this study, we found that in the hypoxia-induced pulmonary hypertension model, lung HIMF expression is increased in IL-4 and STAT6 knockout (KO) mice to the same degree as in wild-type (WT) mice, suggesting that induction of HIMF expression does not require Th2 regulation in this model. We also found that HIMF-induced proliferative activity, hypertrophy, collagen, and extracellular matrix deposition in the pulmonary arteries are significantly less in IL-4 KO mice than in WT mice. In addition, HIMF-induced production of angiogenic factors/chemokines, such as vascular endothelial growth factor, MCP-1, and stromal-derived factor-1, in the lung resident cells, as well as macrophage infiltration, were significantly suppressed in the lungs of IL-4 KO mice. We also show that IL-4 was significantly increased in the lungs of HIMF-treated WT mice. Our in vitro studies using pulmonary microvascular endothelial cells revealed that HIMF stimulated cell proliferation, vascular endothelial growth factor expression, and MCP-1 production in a manner that is dependent on the IL-4/IL-4Ralpha system. These findings suggest that IL-4 signaling may play a significant role in HIMF-induced lung inflammation and vascular remodeling. |
