Neuregulin‐1β Alters the Context‐dependent Production of Immunomodulatory Factors in Human Ventricular Fibroblasts

Abstract

Neuregulin‐1β (NRG‐1β) is a growth and survival factor critical for cardiac development and repair. We recently showed that NRG‐1β reduces cardiac fibrosis in infarcted swine and reduces basal and tumor necrosis factor β (TGFβ)‐induced α‐smooth muscle actin (α‐SMA) expression. In normal human ventricular fibroblasts, we also found that NRG‐1β caused a reduction in TGFβ‐induced α‐SMA, but we did not observe significantly lower α‐SMA levels in response to NRG‐1β under basal conditions. We thus hypothesized that the anti‐fibrotic effects of NRG‐1β might be context dependent. Indeed, when primary rat cardiac fibroblasts were cultured on softer substrates NRG‐1β had little effect on α‐SMA expression. NRG‐1β did not alter fibroblast collagen gel contraction in the presence or absence of TGFβ, nor did NRG‐1β treatment alter proliferation or viability of rodent or human fibroblasts. Nonetheless, these cells expressed all three NRG‐1β receptors (ErbB2, 3, and 4), and NRG‐1β alone reduced transcript levels of tumor necrosis factor‐α (TNF‐α) and prominin 1 (CD133) after 2 hours of treatment in the absence of serum. NRG‐1β inhibition of CXCL10, HLA‐DQB1, and adiponectin (ADIPOQ) on the other hand required the presence of TGFβ, as did NRG‐1β‐mediated increase of the TGFβ‐signaling inhibitor SMAD7. Most interesting was the induction of IL10 transcription in response to the combination of NRG‐1β and TGFβ, neither of which had any effect on IL10 transcript levels in the absence of the other. These results suggest that NRG‐1β modulates inflammation via cardiac fibroblast signaling and moreover that these signaling events are context‐dependent.Work was supported by the NIH (K01 HL121045; U01 HL100398).