Data Sheet 2_Pharmacological inhibition of IL12β is effective in treating pressure overload-induced cardiac inflammation and heart failure.pdf

Background and objectiveEmerging evidence indicates that inflammation regulates cardiac remodeling and heart failure (HF). IL12β is a subunit for proinflammatory cytokines IL12 and IL23. However, the effect of IL12β inhibition on HF development and the underlying mechanism is not understood.
MethodsWe determined the effect of pharmacological inhibition of IL12β using IL12β blocking antibody on transverse aortic constriction (TAC)-induced left ventricular (LV) inflammation and HF development.
ResultsIL12β blocking antibody significantly attenuated TAC-induced LV immune cell infiltration, hypertrophy, fibrosis, dysfunction, and the consequent pulmonary inflammation and remodeling. More specifically, we found that IL12β blocking antibody significantly attenuated TAC-induced LV and pulmonary infiltration of neutrophils, macrophages, CD11c+ dendritic cells, CD8+ T cells, and CD4+ T cells. Moreover, IL12β blocking antibody significantly suppressed the production of pro-inflammatory cytokine pro-IL1β and IFNγ by macrophages and IFNγ by CD8+ T cells and/or CD4+ T cells.
ConclusionsThese findings indicate that pharmacological inhibition of IL12β effectively protected the heart from systolic overload-induced inflammation, remodeling, and dysfunction by reducing the proinflammatory signaling from both innate and adaptive immune responses.

研究背景与目的：越来越多的研究证据表明，炎症可调控心肌重构与心力衰竭（heart failure, HF）。IL12β是促炎细胞因子IL12与IL23的亚基。然而，目前尚不清楚IL12β抑制对心力衰竭发生发展的作用及其潜在机制。研究方法：本研究采用IL12β阻断抗体对IL12β进行药理学抑制，以此探究其对主动脉弓缩窄（transverse aortic constriction, TAC）诱导的左心室（left ventricular, LV）炎症及心力衰竭发生发展的影响。研究结果：IL12β阻断抗体可显著减轻TAC诱导的左心室免疫细胞浸润、心肌肥厚、纤维化、功能障碍，以及由此引发的肺部炎症与重构。更具体地，本研究发现IL12β阻断抗体可显著减轻TAC诱导的左心室与肺部中性粒细胞、巨噬细胞、CD11c+树突状细胞、CD8+ T细胞及CD4+ T细胞的浸润。此外，IL12β阻断抗体可显著抑制巨噬细胞产生促炎细胞因子pro-IL1β与IFNγ，以及CD8+ T细胞和/或CD4+ T细胞产生IFNγ。研究结论：本研究结果表明，通过削弱先天免疫与适应性免疫介导的促炎信号通路，IL12β的药理学抑制可有效保护心脏免受收缩负荷过载诱导的炎症、重构及功能损伤。