Published online before print July 7, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0404221v1 76/3/676    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kahlenberg, J. M. Articles by Dubyak, G. R. Search for Related Content PubMed PubMed Citation Articles by Kahlenberg, J. M. Articles by Dubyak, G. R.

(Journal of Leukocyte Biology. 2004;76:676-684.)
© 2004 by Society for Leukocyte Biology

Differing caspase-1 activation states in monocyte versus macrophage models of IL-1ß processing and release

J. Michelle Kahlenberg^* and George R. Dubyak^,1

^* Department of Pathology and
Department of Physiology and Biophysics, Case School of Medicine, Cleveland, Ohio

¹ Correspondence: Department of Physiology and Biophysics, Case School of Medicine, 2109 Adelbert Road, Cleveland, OH, 44106. E-mail: george.dubyak{at}case.edu

The release of IL-1ß 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-1ß 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-1ß processing in the latter preparation. The transferable activation factor(s) was heat-labile, 10 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-1ß 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-1ß processing and release in various model systems.

Key Words: AG126 • bromoenol lactone • inflammation

This article has been cited by other articles:

				M. A. Gavrilin, S. Mitra, S. Seshadri, J. Nateri, F. Berhe, M. W. Hall, and M. D. Wewers Pyrin Critical to Macrophage IL-1{beta} Response to Francisella Challenge J. Immunol., June 15, 2009; 182(12): 7982 - 7989. [Abstract] [Full Text] [PDF]

				N. Molnarfi, L. Gruaz, J.-M. Dayer, and D. Burger Opposite Regulation of IL-1beta and Secreted IL-1 Receptor Antagonist Production by Phosphatidylinositide-3 Kinases in Human Monocytes Activated by Lipopolysaccharides or Contact with T Cells J. Immunol., January 1, 2007; 178(1): 446 - 454. [Abstract] [Full Text] [PDF]

				J. M. Kahlenberg, K. C. Lundberg, S. B. Kertesy, Y. Qu, and G. R. Dubyak Potentiation of Caspase-1 Activation by the P2X7 Receptor Is Dependent on TLR Signals and Requires NF-{kappa}B-Driven Protein Synthesis J. Immunol., December 1, 2005; 175(11): 7611 - 7622. [Abstract] [Full Text] [PDF]