Abstract
Although IL-1beta is the master inflammatory cytokine in the IL-1 family, after more than ten years of continuous breeding, mice deficient in IL-1beta exhibit no spontaneous disease. Therefore, one concludes that IL-1beta is not needed for homeostasis. However, IL-1beta-deficient mice are protected against local and systemic inflammation due to live infections, autoimmune processes, tumor metastasis and even chemical carcinogenesis. Based on a large number of preclinical studies, blocking IL-1beta activity in humans with a broad spectrum of inflammatory conditions has reduced disease severity and for many, has lifted the burden of disease. Rare and common diseases are controlled by blocking IL-1beta. Immunologically, IL-1beta is a natural adjuvant for responses to antigen. Alone, IL-1beta is not a growth factor for lymphocytes; rather in antigen activated immunocompetent cells, blocking IL-1 reduces IL-17 production. IL-1beta markedly increases in the expansion of naive and memory CD4T cells in response to challenge with their cognate antigen. The response occurs when only specific CD4T cells respond to IL-1beta and not to IL-6 or CD-28. A role for autophagy in production of IL-1beta has emerged with deletion of the autophagy gene ATG16L1. Macrophages from ATG16L1-deficient mice produce higher levels of IL-1beta after stimulation with TLR4 ligands via a mechanism of caspase-1 activation. The implications for increased IL-1beta release in persons with defective autophagy may have clinical importance for disease.
