Hypoxia-Induced Mitogenic Factor (HIMF/FIZZ1/RELMα) 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.

Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

“…48,[57][58][59][60] As an explanation for our unexpected data, the role of RELMα in arterial thickening and remodeling could vary depending on the type of challenge (e.g., hypoxia vs. antigen). 48,61 Comparing the data shown in Figures 5 and 6 suggests that airway eosinophils, neutrophils, myeloid cell activation markers S100a8 and S100a9, and IL-6 are not critical promoters of the severe arterial remodeling response and that IFN-γ is not a critical inhibitor. With respect to the role of IL-6 in severe pulmonary arterial thickening, it is of great interest that in experimental schistosomiasis the IL-6 pathway has recently been shown to have a protective function.…”

Resistin-Like Molecule α Stimulates Proliferation of Mesenchymal Stem Cells While Maintaining Their Multipotency

“…RELMa has been shown to induce proliferation of vascular smooth muscle cells and endothelial cells [1,31]. Our previous work suggested that RELMa also exerts a chemokine effect on bone marrow progenitor cells.…”

Resistin-Like Molecule alpha Enhances the Proliferation and Migration of Aortic Vascular Smooth Muscle Cells

“…RELMα is a members of the family of resistin-like molecules which is thought to play an important role in pulmonary fibrosis, asthma, hypoxia and silicosis [6,11,12,13]. Further studies have shown thatresistin-like molecules may be involved in the formation of foam cells and the development of angiogenesis and thrombosis, indicating that they support the progression of atherosclerosis [5,14].…”

“…Studies have shown that it also has angiogenic and vasoconstrictive properties [5] and that it increases pulmonary arterial pressure and vascular resistance more potently than either endothelin-1 or angiotensin II [6]. …”

“…This in turn causes mononuclear cells to bind to endothelial cells, which promotes the formation of foam cells, and participates in the progression of atherosclerosis [6]. …”