Targeting Interleukin-1 in Heart Disease

Inflammation is a coordinated cellular-humoral response to injury. A close interaction between resident cells (ie, endothelial cells, fibroblasts, and dendritic cells) and leukocytes regulates the initiation and resolution of the acute inflammatory response. Constitutive membrane and cytoplasmic receptors function as guardians that “signal the alarm” when activated by products of cell destruction or microbial invasion. This first-line innate immune response initiates a process of leukocyte mobilization from the bone marrow, recruitment to the “activated” endothelium, and migration to the site of tissue injury to prevent infection and to facilitate tissue repair. Although critical for many forms of repair, the inflammatory response may also become a mechanism for progressive injury, impaired healing, and disease.Interleukin-1 (IL-1) is an apical proinflammatory mediator in acute and chronic inflammation and a powerful inducer of the innate immune response.1,2 The production and activity of IL-1 are finely regulated at multiple levels, and very small concentrations of exogenous IL-1 can induce a sepsis-like syndrome and shock.1,2 IL-1 induces the synthesis and expression of several hundreds of secondary inflammatory mediators.1,2 IL-1 also induces its own production and processing, and this step is key in the pathogenesis of many autoinflammatory diseases.1,3 Two related genes code for 2 different proteins (IL-1α and IL-1β) that bind the same receptor (type I). IL-1α is synthesized as a fully active peptide that remains membrane bound or may be released from the cytoplasm during cell death. IL-1α thereby participates more prominently in local response to injury and less in the systemic inflammatory response.1,2 IL-1β, the main form of circulating IL-1, is initially synthesized as a precursor (proIL-1β) that becomes activated by caspase-1 cleavage in the setting of a macromolecular structure known as the inflammasome.1,4 Caspase-1 …