{"doi":"10.3389/fimmu.2020.01910","title":"Heme Induces IL-6 and Cardiac Hypertrophy Genes Transcripts in Sickle Cell Mice","abstract":"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 µmoles/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.","journal":"Frontiers in Immunology","year":2020,"id":102559,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9456,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":423329,"name":"Maria G. Kapetanaki","orcid":null,"position":1,"is_corresponding":false},{"id":422529,"name":"Samit Ghosh","orcid":"0000-0002-3536-3077","position":2,"is_corresponding":false},{"id":364203,"name":"Flordeliza S. Villanueva","orcid":"0000-0003-3980-9176","position":3,"is_corresponding":false},{"id":422530,"name":"Solomon F. Ofori‐Acquah","orcid":"0000-0001-5000-3048","position":4,"is_corresponding":false},{"id":369011,"name":"Gregory J. Kato","orcid":"0000-0003-4465-3217","position":5,"is_corresponding":false},{"id":422528,"name":"Oluwabukola T. Gbotosho","orcid":"0000-0002-9176-7025","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T22:41:53.173268Z","pmid":"32973791","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}