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 (50%) 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.