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Interleukin‐6 Trans‐signaling Contributes to Chronic Hypoxia‐induced Pulmonary Hypertension
Author(s) -
Maston Levi D,
Jones David T,
Giermakowska Wieslawa,
Resta Thomas C,
Bosc Laura Gonzalez
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1016.20
Subject(s) - pulmonary hypertension , glycoprotein 130 , hypoxia (environmental) , endocrinology , signal transduction , medicine , cytokine , receptor , lung , inflammation , immunology , biology , chemistry , microbiology and biotechnology , interleukin 6 , organic chemistry , oxygen
Interleukin‐6 (IL‐6) is a pleotropic cytokine that signals through the membrane‐bound IL‐6 receptor (mIL‐6R) to induce anti‐inflammatory (“classic‐signaling”) responses. This cytokine also binds to the soluble IL‐6R (sIL‐6R) to promote inflammation (“trans‐signaling”). mIL‐6R expression is restricted to hepatocytes and immune cells. However, activated T cells release sIL‐6R into adjacent tissues to induce trans‐signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. IL‐6 is produced by pulmonary arterial smooth muscle cells exposed to chronic hypoxia (CH) and IL‐6 knockout mice are protected from CH‐induced pulmonary hypertension (PH). IL‐6, through the activation of STAT1 and STAT3 has the potential to contribute to a broad array of downstream effects, such as cell growth and migration. CH‐induced PH is associated with increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) to previously non‐muscularized vessels of the lung. Therefore, we hypothesized that IL‐6 trans‐signaling contributes to CH‐induced pulmonary hypertension and arterial remodeling. To test this hypothesis, C57BL/6J mice were chronically administered the IL‐6 trans‐signaling‐specific inhibitor sgp130Fc (0.5 mg/kg i.p., twice/wk; R&D Systems) or vehicle and exposed to either normoxia (630 mmHg, Albuquerque, NM) or CH (380 mmHg) for 3 weeks. Right ventricular systolic pressure (RVSP) was recorded in isoflurane‐anesthetized mice, and percent pulmonary arterial wall thickness was determined as an index of pulmonary vascular remodeling. Plasma levels of sIL‐6R and endogenous gp130 (natural specific inhibitor of IL‐6 trans‐signaling) were measured by ELISA. In addition, PASMC migration was evaluated using a scratch‐wound healing assay and proliferation assessed by measuring culture confluency over time, normalized to initial confluency (IncuCyte, Essen BioSciences) in the presence or absence of IL‐6/sIL‐6R, with or without sgp130Fc. Consistent with our hypothesis, sgp130Fc treatment attenuated CH‐induced increases in RVSP ( Fig. A) and pulmonary arterial remodeling ( Fig. B) as compared to vehicle (saline)‐treated control mice. Plasma levels of sgp130 were significantly decreased in mice exposed to CH for 5 days as compared to normoxic control mice, while sIL‐6R levels were unchanged. In addition, PASMC cultured in the presence of IL‐6 and sIL‐6R showed enhanced migration ( Fig. C) but not proliferation ( Fig. D) compared to those treated with IL‐6 or sIL‐6R alone or in the presence of sgp130Fc. These results indicate that IL‐6 trans‐signaling contributes to pulmonary arterial cell migration and CH‐induced PH. Support or Funding Information NIH R01 HL132883 and AHA 16GRNT27700010 (TCR). NIH F30 HL123109 (LDM). AHA 15GRNT25090039 (LGB)Figures A and B: *p<0.05 vs. normoxia; #p<0.05 vs. CH vehicle; n=6. Figures C and D: *p<0.05 vs. control; n=15