Published online before print July 7, 2004
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processing and release
@
*Department of Pathology andDepartment of Physiology and Biophysics, Case School of Medicine, Cleveland, Ohio
@ To whom correspondence should be addressed. E-mail: george.dubyak{at}case.edu.
The release of IL-1
as an active, mature cytokine requires proteolytic processing by caspase-1, which is recruited to signaling complexes that facilitate its autocatalytic proteolysis and activation. Caspase-1 processing has been characterized in human monocyte and murine macrophage model systems, and comparative analyses indicate significant mechanistic differences in caspase-1 activation by these cell types. In this study, we used an in vitro processing assay to compare caspase-1 activation in THP-1 human monocytes vs. Bac1.2F5 murine macrophages. These in vitro caspase-1 and IL-1 processing reactions indicated a higher rate of constitutive caspase-1 activation in lysates from THP-1 vs. Bac1 cells. Transfer of small amounts of THP-1 lysate to Bac1 lysate rapidly increased in vitro procaspase-1 and proIL-1 processing in the latter preparation. The transferable activation factor(s) was heat-labile, 310 kDa, and unaffected by immunodepletion of procaspase-1 from the THP-1 lysate. This transactivating effect of THP-1 lysate on processing in Bac1 lysates could be mimicked by addition of purified recombinant human caspase-1. The constitutive caspase-1 and IL-1 processing reactions in THP-1 lysates were insensitive to pharmacological blockade by the tyrphostin, AG126, and the phospholipase A2 inhibitor bromoenol lactone (BEL); contrarily, the same processing reactions were inhibited in lysates from Bac1 cells pretreated with either AG126 or BEL. These observations indicate significant biochemical differences in the assembly and regulation of caspase-1 signaling complexes within human monocyte and murine macrophage models of inflammatory activation. These differences need to be considered when comparing or pharmacologically manipulating IL-1 processing and release in various model systems.
Key Words: AG126 • bromoenol lactone • inflammation
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