10.25376/hra.7794122.v1 Levi Maston Levi Maston David T Jones David T Jones Wieslawa Giermakowska Wieslawa Giermakowska Thomas C. Resta Thomas C. Resta Juan M. Ramiro Diaz Juan M. Ramiro Diaz Tamara A Howard Tamara A Howard Nikki L. Jernigan Nikki L. Jernigan Lindsay M. Herbert Lindsay M. Herbert Anna A. Maurice Anna A. Maurice Laura Gonzalez bosc Laura Gonzalez bosc Interleukin-6 trans-signaling contributes to chronic hypoxia-induced pulmonary hypertension Health Research Alliance 2019 hypoxia IL-6 pulmonary vasculature sgp130 sIL-6R Physiology 2019-03-01 21:28:05 Journal contribution https://hra.figshare.com/articles/journal_contribution/Interleukin-6_trans-signaling_contributes_to_chronic_hypoxia-induced_pulmonary_hypertension/7794122 Interleukin-6 (IL-6) is a pleotropic cytokine that signals through the membrane-bound IL-6 receptor (mIL-6R) to induce antiinflammatory<br>(‘‘classic-signaling’’) responses. This cytokine also binds to the soluble IL-6R (sIL-6R) to promote inflammation<br>(‘‘trans-signaling’’). mIL-6R expression is restricted to hepatocytes and immune cells. Activated T cells release sIL-6R into adjacent<br>tissues to induce trans-signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. Reports<br>show that IL-6 is produced by pulmonary arterial smooth muscle cells (PASMCs) exposed to hypoxia in culture as well as the<br>medial layer of the pulmonary arteries in mice exposed to chronic hypoxia (CH), and IL-6 knockout mice are protected from CHinduced<br>pulmonary hypertension (PH). IL-6 has the potential to contribute to a broad array of downstream effects, such as cell<br>growth and migration. CH-induced PH is associated with increased proliferation and migration of PASMCs to previously nonmuscularized<br>vessels of the lung. We tested the hypothesis that IL-6 trans-signaling contributes to CH-induced PH and arterial<br>remodeling. Plasma levels of sgp130 were significantly decreased in mice exposed to CH (380 mmHg) for five days compared to<br>normoxic control mice (630 mmHg), while sIL-6R levels were unchanged. Consistent with our hypothesis, mice that received the<br>IL-6 trans-signaling-specific inhibitor sgp130Fc, a fusion protein of the soluble extracellular portion of gp130 with the constant<br>portion of the mouse IgG1 antibody, showed attenuation of CH-induced increases in right ventricular systolic pressure, right<br>ventricular and pulmonary arterial remodeling as compared to vehicle (saline)-treated control mice. In addition, PASMCs cultured<br>in the presence of IL-6 and sIL-6R showed enhanced migration but not proliferation compared to those treated with IL-6 or sIL-6R<br>alone or in the presence of sgp130Fc. These results indicate that IL-6 trans-signaling contributes to pulmonary arterial cell<br>migration and CH-induced PH.