Journal of Biological Chemistry
Volume 270, Issue 46, 17 November 1995, Pages 27758-27765
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Cell Biology and Metabolism
Differential Sensitivity of Interleukin-1α and -β Precursor Proteins to Cleavage by Calpain, a Calcium-dependent Protease (*)

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In view of the observations that the calcium ionophores, A23187 and ionomycin, enhance the processing and secretion of interleukin-1 (IL-1α) and IL-1β from macrophages, and IL-1α processing is mediated by calpain, a calcium-dependent protease, we evaluated the possibility that calpain might also play a role in the processing of IL-1β. Whereas calpain-containing P388D1 macrophage lysates and purified calpain processed precursor IL-1α to its mature 17-kDa form, precursor IL-1β was degraded by both sources of calpain. However, the activation of calpain in P388D1 cells that were transiently transfected with a cDNA expression vector encoding the precursor form of IL-1β did not result in the degradation of precursor IL-1β, but did result in the processing and secretion of IL-1α, implying that precursor IL-1β is protected from calpain degradation in vivo. Furthermore, calpain did not enhance the processing of the IL-1β precursor by the IL-1β-converting enzyme. These results indicate that calpain is not involved in the processing of precursor IL-1β in vitro or in vivo. The IL-1β precursor may be protected from calpain degradation by a sequestering mechanism that involves a cytoplasmic factor(s) that reduces the sensitivity of IL-1β to attack by calpain or localizes IL-1β to a site that precludes any interaction with the protease.

Although MDL 28,170, a calpain inhibitor, prevented the ionomycin-induced processing of precursor IL-1α to the mature protein in P388D1 cells, it did not inhibit the ionomycin-induced secretion of the mature IL-1α and -β proteins expressed in these cells. These results indicate that a calcium-dependent factor other than calpain is involved in the secretion of the mature IL-1 proteins.

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*

This work was supported by National Institutes of Health Grant AI25836 and National Institutes of Health Training Grant AI07401 (to U. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.