title: Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMalpha) increases lung inflammation and activates pulmonary microvascular endothelial cells via an IL-4-dependent mechanism.
abstract: Hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 and resistin-like molecule α, 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-4Rα system. These findings suggest that IL-4 signaling may play a significant role in HIMF-induced lung inflammation and vascular remodeling.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamaji-Kegan
authors.forename: Qingning
authors.initials: Q
authors.lastname: Su
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Angelini
authors.forename: Allen C
authors.initials: AC
authors.lastname: Myers
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C413576:Retnla protein, mouse; D015847:Interleukin-4