Rationale: It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1␤ has also been shown to induce cardiomyocyte hypertrophy. Thus, the role of IL-1 in the heart remains to be determined. Objective: We studied the role of hypertrophy signal-mediated IL-1␤/insulin-like growth factor (IGF)-1 production in regulating the progression from compensative pressure-mediated hypertrophy to heart failure. Methods and Results: Pressure overload was performed by aortic banding in IL-1␤-deficient mice. Primarily cultured cardiac fibroblasts (CFs) and cardiac myocytes (CMs) were exposed to cyclic stretch. Heart weight, myocyte size, and left ventricular ejection fraction were significantly lower in IL-1␤-deficient mice (20%, 23% and 27%, respectively) than in the wild type 30 days after aortic banding, whereas interstitial fibrosis was markedly augmented. DNA microarray analysis revealed that IGF-1 mRNA level was markedly (Ϸ50%) decreased in the IL-1␤-deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1␤ and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1␤-deficient CFs. IL-1␤ released by stretch is at a low level unable to induce IL-6 but sufficient to stimulate IGF-1 production. Promoter analysis showed that stretch-mediated IL-1␤ activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1␤ deficiency markedly increased c-Jun N-terminal kinase (JNK) and caspase-3 activities and enhanced myocyte apoptosis and fibrosis, whereas replacement of IGF-1 or JNK inhibitor restored them. Conclusions: We demonstrate for the first time that pressure-mediated hypertrophy and mechanical stretch generates a subinflammatory low level of IL-1␤, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis. (Circ Res. 2009;105:1149-1158.)Key Words: interleukin-1 Ⅲ insulin-like growth factor-1 Ⅲ Akt Ⅲ JNK Ⅲ hypertrophy C ardiac hypertrophy is defined by augmentation of the ventricular mass against hemodynamic loads and upregulates contractile capacity and reduces ventricular wall stress, 1 whereas the capacity of this compensation is limited, and stronger and longer pressure overload induces pathological cardiac remodeling with left ventricular (LV) dilatation. 1 Pathological cardiac remodeling is associated with production of the extracellular matrix and causes increased signals of myocyte apoptosis. 2 Receptor tyrosine kinase, such as insulin-like growth factor (IGF)-1 receptor is involved in not only physiological hypertrophy 3 but also compensated hypertrophy after pressure overload. 4 IGF-1 promotes myocardial hypertrophy by activating phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt. 5,6 In addition, mitogenactivated protein kinase 7 acts as downstream molecules to promote hypertrophy.Overexpression of G protein-coupled 7-transmembrane receptors in the heart induced cardiac remodeling, resulting in he...

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