NO-Releasing NSAIDs Modulate Cytokine Secretion

Abstract

IL-1β-converting enzyme (ICE, caspase-1) is the prototype of a family of cysteine proteases termed caspases, sharing the active site cysteine and aspartate binding clefts. The biological function of caspase-1 was originally thought to be restricted to the maturation process of IL-1β, a central mediator in the cytokine network. Proteolytic maturation of the inactive, 33-kD IL-1β precursor (proIL-1β) into the 17-kD, biologically functional form results from cleavage at the Asp¹¹⁶-A1a¹¹⁷ site [1,2]. However, recent studies revealed that caspase-1 mediates processes relevant to immune and inflammatory reactions, in addition to IL-1β activation. The enzyme has been implicated in the activation of another inflammatory cytokine, IL-18, originally termed IFN-γ inducing factor (IGIF). Similar to IL-1β, IL-18 is expressed as an inactive precursor (24 kD), requiring proteolytic conversion via caspase-1 into the active, 18-kD form. The biological function of IL-18 was originally thought to be restricted to the induction of another inflammatory cytokine, IFN-, which has well-known roles in inflammation and Thl immune responses. However, recent work indicated a much broader role for IL-18 in immunity and inflammation, mediating the expression of other proinflammatory cytokines, certain chemokines, and Fas ligand. In addition to the activation of proinflammatory mediators, caspase-1 is the prototype of a family of enzymes implicated in the control of apoptosis. Although the exact function of caspase-1 is controversial, this enzyme may participate in programmed cell death. In recent years ICE has been recognized as a member of the growing family of intracellular cysteine proteases that share sequence homology with Ced-3, a nematode gene involved in the execution phase of apoptosis [3–5]. The mammalian counterpart of the Ced-3 gene products includes at least 14 different endoproteases that have been renamed caspases to denote cysteine proteases acting after an aspartic acid residue. Caspase-1, which has the greatest specificity for cleaving proIL-β, denotes the original ICE (both terms are often used interchangeably).