| First Author | Gbotosho OT | Year | 2020 |
| Journal | Front Immunol | Volume | 11 |
| Pages | 1910 | PubMed ID | 32973791 |
| Mgi Jnum | J:302762 | Mgi Id | MGI:6510167 |
| Doi | 10.3389/fimmu.2020.01910 | Citation | Gbotosho OT, et al. (2020) Heme Induces IL-6 and Cardiac Hypertrophy Genes Transcripts in Sickle Cell Mice. Front Immunol 11:1910 |
| abstractText | Emerging data indicate that free heme promotes inflammation in many different disease settings, including in sickle cell disease (SCD). Although free heme, proinflammatory cytokines, and cardiac hypertrophy are co-existing features of SCD, no mechanistic links between these features have been demonstrated. We now report significantly higher levels of IL-6 mRNA and protein in hearts of the Townes sickle cell disease (SS) mice (2.9-fold, p </= 0.05) than control mice expressing normal human hemoglobin (AA). We find that experimental administration of heme 50 mumoles/kg body weight induces IL-6 expression directly in vivo and induces gene expression markers of cardiac hypertrophy in SS mice. We administered heme intravenously and found that within three hours plasma IL-6 protein significantly increased in SS mice compared to AA mice (3248 +/- 275 vs. 2384 +/- 255 pg/ml, p </= 0.05). In the heart, heme induced a 15-fold increase in IL-6 transcript in SS mice heart compared to controls. Heme simultaneously induced other markers of cardiac stress and hypertrophy, including atrial natriuretic factor (Nppa; 14-fold, p </= 0.05) and beta myosin heavy chain (Myh7; 8-fold, p </= 0.05) in SS mice. Our experiments in Nrf2-deficient mice indicate that the cardiac IL-6 response to heme does not require Nrf2, the usual mediator of transcriptional response to heme for heme detoxification by heme oxygenase-1. These data are the first to show heme-induced IL-6 expression in vivo, suggesting that hemolysis may play a role in the elevated IL-6 and cardiac hypertrophy seen in patients and mice with SCD. Our results align with published evidence from rodents and humans without SCD that suggest a causal relationship between IL-6 and cardiac hypertrophy. |
