Human RELMβ is a mitogenic factor in lung cells and induced in hypoxia

Renigunta, Aparna; Hild, Christiane; Rose, Frank; Klepetko, Walter; Grimminger, Friedrich; Seeger, Werner; Hänze, Jörg

doi:10.1016/j.febslet.2006.01.012

Cited by 38 publications

(51 citation statements)

References 12 publications

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“…The dilated crypt structures lined with isolated goblet cells suggest that, in the absence of RELMβ, the colonic epithelium and its associated crypt structures may either be better able to survive destruction or may be more rapidly reconstituted in the setting of intestinal inflammation. Although recent evidence that RELMβ acts as a mitogenic factor in lung epithelium via a PI3K-dependent mechanism might be consistent with this notion (21), there was no difference in epithelial apoptosis, which was very rare, as determined by TUNEL staining, in both wild-type and RELMβ -/-mice that received DSS (data not shown). Alternatively, the RELMβ-null mice may be more resistant to the initiation of disease induced by DSS.…”

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confidence: 53%

Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis

et al. 2006

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Section: Figuresupporting

confidence: 53%

Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis

et al. 2006

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“…Furthermore, mouse RELMα and its human homologue, RELMβ, are known as hypoxia-induced mitogenic factors and are smooth muscle cell mitogens. 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.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen-and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule α. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13-and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13-and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune response-induced pulmonary hypertension.

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“…A recent study has suggested that human RELM␤ also has mitogenic action on human lung cells, and this protein may contribute to pulmonary vascular remodeling and fibrotic lung disease (30). Considering the limitations of current treatment of PH (9), inhibition of HIMF might be considered to prevent or reduce lung inflammation as well as hypoxia-induced PH.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2

Yamaji-Kegan¹,

Su²,

Angelini³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

102

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. Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol 291: L1159 -L1168, 2006. First published August 4, 2006 doi:10.1152/ajplung.00168.2006-From a mouse model of hypoxiainduced pulmonary hypertension, we previously found a highly upregulated protein in the lung that we named hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 (FIZZ1), and resistin-like molecule ␣ (RELM␣). However, the mechanisms of HIMF in the pulmonary vascular remodeling remain unknown. We now demonstrate that HIMF promoted cell proliferation, migration, and the production of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) in pulmonary endothelial cells as well as the production of reactive oxygen species in murine monocyte/macrophage cells. HIMF-induced CD31-positive cell infiltrate in in vivo Matrigel plugs was significantly suppressed by VEGF receptor-2 (VEGFR2) blockade. In ex vivo studies, HIMF stimulated the production of VEGF, MCP-1, and stromal cell-derived factor-1 (SDF-1) in the lung resident cells, and VEGFR2 neutralization significantly suppressed HIMF-induced MCP-1 and SDF-1 production. Furthermore, intravenous injection of HIMF showed marked increase of CD68-positive inflammatory cells in the lungs, and these events were attenuated by VEGFR2 neutralization. Intravenous injection of HIMF also downregulated the expression of VEGFR2 in the lung. These results suggest that HIMF plays critical roles in pulmonary inflammation as well as angiogenesis. vascular endothelial growth factor; monocyte chemotactic protein-1; vascular endothelial growth factor receptor-2; pulmonary inflammation; hypoxia-induced mitogenic factor; found in inflammatory zone 1; resistin-like molecule ␣ PULMONARY HYPERTENSION (PH) is a serious disease of poorly understood etiology characterized by raised pulmonary artery pressure, leading to progressive right-sided heart failure and ultimately death (32). PH results from intimal thickening of small pulmonary resistance arteries that results, at least in part, from endothelial and smooth muscle cell dysfunction and proliferation (41). Increased vascular endothelial cell (EC) proliferation and muscularization of the vasculature are the pathological characteristics of pulmonary vascular remodeling, and it has been demonstrated that this process is associated with hypoxia-induced production of angiogenic factors, inflammatory mediators, and vasoconstrictors.From a mouse model of hypoxia-induced PH, we previously found a highly upregulated protein that we named hypoxiainduced mitogenic factor (HIMF) (37). A microarray study showed that HIMF gene was significantly upregulated in the lungs of mice that were exposed to hypoxia for 1-4 days. We demonstrated that the recombinant protein of this gene has mitogenic actions and stimulated pulmonary microvascular smooth muscle cell proliferation via an Akt-dependent pathway.

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Human RELMβ is a mitogenic factor in lung cells and induced in hypoxia

Cited by 38 publications

References 12 publications

Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis

Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis

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

Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2

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