IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice.
Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction.
Surgery Department and Sarver Heart Center, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Qianli
Q
Yu
Randy
R
Vazquez
Elham Vali
EV
Khojeini
Chirag
C
Patel
Raj
R
Venkataramani
Douglas F
DF
Larson
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001810:Blood Volume / Q000502:physiology; D002469:Cell Separation; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology*; D054144:Heart Failure, Diastolic / Q000139:chemically induced* / Q000473:pathology*; D006909:Hydroxyproline / Q000737:chemistry / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology; D020382:Interleukin-18 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology; D009206:Myocardium / Q000473:pathology*; D053495:Osteopontin / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects
D050835:Interferon Regulatory Factors; D020382:Interleukin-18; D012333:RNA, Messenger; D053495:Osteopontin; D003094:Collagen; D006909:Hydroxyproline