Abstract 3865: Interleukin-18 is a Potent Inducer of EMMPRIN Expression Both in vitro and in vivo, and Their Crosstalk Induces MMP9 Expression via PI3K-Akt-IKK-NF-κB Signaling
Introduction: We have shown that interleukin (IL)-18 plays a role in myocardial injury and remodeling via induction of matrix metalloproteinases (MMPs) and other proinflammatory cytokines. Since the matricellular protein EMMPRIN (basigin/CD147) is a potent inducer of MMPs, we investigated if IL-18 and EMMPRIN expression is cross-regulated, and whether IL-18-induced MMP9 expression is EMMPRIN-dependent.
Methods and results: IL-18 potently induced EMMPRIN expression and secretion in adult mouse cardiomyocytes (ACM; inhibited by IL-18 neutralizing antibodies and IL-18BP-Fc). IL-18 stimulated both Sp1 and NF-κB activations in ACM. In neonatal mouse cardiomyocytes (NMCM), IL-18 stimulated EMMPRIN promoter activity was inhibited by mithramycin and over-expressed mutant Sp1, but not by dominant negative (dn) p65, dnIκB-α, or kdIKKβ. Mutation of the Sp1 binding sites blunted IL-18-stimulated EMMPRIN promoter activity. Transduction with adenoviral dominant negative constructs showed that IL-18 mediated Sp1 activation and EMMPRIN induction through a MyD88/IRAK/TRAF6/JNK2 pathway. In contrast, similar approaches showed that EMMPRIN induced IL-18 via PI3K, Akt, IKK, and NF-κB. Importantly, both IL-18 and EMMPRIN induced MMP9 mRNA, protein, enzyme activity and promoter activity via NF-κB activation. EMMPRIN knockdown partially inhibited IL-18-induced MMP9 expression. IL-18 and EMMPRIN had no affect on cardiomyocyte viability, but IL-18 (not EMMPRIN) induced cardiomyocyte hypertrophy via PI3K-Akt-p70S6K signaling. Administration of IL-18, but not neutralized IL-18, daily for 7 days recapitulated IL-18 effects in vitro by inducing cardiomyocyte hypertrophy (increased cross-sectional area), enhanced EMMPRIN expression (localized to cardiomyocyte sarcolemma), and increased MMP9 expression and activity in LV extracts.
Conclusions: Our studies define an IL-18-EMMPRIN-MMP9 pathway in myocardial remodeling. IL-18 and EMMPRIN regulate each other’s expression and induce MMP9 in an NF-κB-dependent manner. Since IL-18 induces MMP9 expression in part via EMMPRIN, and IL-18 but not EMMPRIN induces cardiomyocyte hypertrophy, IL-18 is a potential therapeutic target in post-infarct myocardial injury, hypertrophy and remodeling.