Regulation of the expression and processing of caspase-12

Abstract

Phylogenetic analysis clusters caspase-12 with the inflammatory caspases 1 and 11. We analyzed the expression of caspase-12 in mouse embryos, adult organs, and different cell types and tested the effect of interferons (IFNs) and other proinflammatory stimuli. Constitutive expression of the caspase-12 protein was restricted to certain cell types, such as epithelial cells, primary fibroblasts, and L929 fibrosarcoma cells. In fibroblasts and B16/B16 melanoma cells, caspase-12 expression is stimulated by IFN-γ but not by IFN-α or -β. The effect is increased further when IFN-γ is combined with TNF, lipopolysaccharide (LPS), or dsRNA. These stimuli also induce caspase-1 and -11 but inhibit the expression of caspase-3 and -9. In contrast to caspase-1 and -11, no caspase-12 protein was detected in macrophages in any of these treatments. Transient overexpression of full-length caspase-12 leads to proteolytic processing of the enzyme and apoptosis. Similar processing occurs in TNF-, LPS-, Fas ligand–, and thapsigargin (Tg)-induced apoptosis. However, B16/B16 melanoma cells die when treated with the ER stress–inducing agent Tg whether they express caspase-12 or not.

Inflammatory caspases and inflammasomes: master switches of inflammation

“…39,40 Whereas degradation or proteolysis of caspase-12 is a well-established hallmark of ER stress, its central role in ER-stress-induced apoptosis was challenged by various studies. [41][42][43] The precise function of caspase-12 in this particular pathway is yet unclear and controversial.…”

Caspase-12: an overview

“…7 The induction of caspase-12 is specific for IFN-g and does not occur with IFN-a or -b. 7 However, the exact role of caspase-12 in these cells remains elusive. Generation of caspase-12-deficient mice by replacement of a segment of intron 3 and exon 4 with a neomycin gene has been reported 3 years ago.…”

“…Moreover, in contrast to caspase-1 and -11, no caspase-12 protein expression or induction was detected in macrophage cell lines, or in isolated primary macrophages. 7 The absence of caspase-12 in macrophages, the inflammatory cells par excellence, suggests that the protein has a function distinct from that of caspase-1 and -11. Though induction of caspase-12 expression in macrophages in response to certain proinflammatory stimuli remains possible, caspase-12 may have a function related to inflammation in cells other than macrophages.…”

“…Indeed, constitutive expression of caspase-12 has been observed in primary fibroblasts and in the L929 and AKR-2B fibrosarcoma cell lines. 7,8 Moreover, it was reported that the mRNA of caspase-12 is induced by the proinflammatory cytokine IFN-g in primary hepatocytes 9 and the caspase-12 protein in murine primary fibroblasts, L929 fibrosarcoma and B16/B16 melanoma cells. 7 The induction of caspase-12 is specific for IFN-g and does not occur with IFN-a or -b.…”

“…7,8 Moreover, it was reported that the mRNA of caspase-12 is induced by the proinflammatory cytokine IFN-g in primary hepatocytes 9 and the caspase-12 protein in murine primary fibroblasts, L929 fibrosarcoma and B16/B16 melanoma cells. 7 The induction of caspase-12 is specific for IFN-g and does not occur with IFN-a or -b. 7 However, the exact role of caspase-12 in these cells remains elusive.…”