QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) An erratum has been published Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Verhoef, P. A. Articles by Dubyak, G. R. Search for Related Content PubMed PubMed Citation Articles by Verhoef, P. A. Articles by Dubyak, G. R.

Maitotoxin Induces Biphasic Interleukin-1 Secretion and Membrane Blebbing in Murine Macrophages

Departments of Pharmacology (P.A.V., G.R.D.) and Physiology and Biophysics (S.B.K., W.P.S., G.R.D.), Case Western Reserve University School of Medicine, Cleveland, Ohio; and the Rammelkamp Center for Education and Research at MetroHealth Medical Center (M.E., W.P.S.), Cleveland, Ohio

Maitotoxin (MTX) is a potent shellfish toxin widely used as an in vitro tool for increasing intracellular Ca²⁺ and studying Ca²⁺-dependent processes. MTX also induces membrane blebbing and nonselective pores similar to those elicited by the P2X7 receptor (P2X7R), an ATP-gated cation channel expressed in inflammatory leukocytes. We therefore tested whether MTX treatment of lipopolysaccharide-primed murine macrophages would mimic the ability of activated P2X7R to induce secretion of the proinflammatory cytokine interleukin-1 (IL-1). MTX at 0.6 nM predominantly induced processing and nonlytic release of mature IL-1 (mIL-1), whereas >0.6 nM of MTX induced cytolytic release of unprocessed proIL-1. MTX-dependent release of mIL-1 (but not cytolysis) was inhibited by the elimination of the trans-plasma membrane K⁺ gradient. MTX-induced cytokine release and cytolysis were both abrogated in the absence of extracellular Ca²⁺. On the other hand, extracellular glycine (5 mM) blocked MTX-induced cytolytic release of proIL-1 without affecting regulated secretion of mIL-1. Because MTX has profound effects on plasma membrane permeability, we used time-lapse videography to examine the morphologic response of individual macrophages to MTX. MTX treatment led to biphasic propidium dye uptake and dilated blebbing coincident with cytolysis. Glycine completely blocked the second, lytic phase of dye uptake and prevented MTX-induced bleb dilation. These results indicate that the inflammatory macrophage can assemble the necessary signaling components to initiate both regulated and lytic release of IL-1 in response to MTX. This suggests that the hyperactivation of proinflammatory cytokine secretion may be a significant component of the in vivo response to MTX during shellfish seafood poisoning.

Address correspondence to: Dr. George R. Dubyak, Department of Physiology and Biophysics, School of Medicine Room E565, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4970. E-mail: gxd3{at}po.cwru.edu

This article has been cited by other articles:

				Y. Qu, L. Franchi, G. Nunez, and G. R. Dubyak Nonclassical IL-1beta Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages J. Immunol., August 1, 2007; 179(3): 1913 - 1925. [Abstract] [Full Text] [PDF]

				P. Pelegrin and A. Surprenant Pannexin-1 Couples to Maitotoxin- and Nigericin-induced Interleukin-1beta Release through a Dye Uptake-independent Pathway J. Biol. Chem., January 26, 2007; 282(4): 2386 - 2394. [Abstract] [Full Text] [PDF]

				W. P. Schilling, D. Snyder, W. G. Sinkins, and M. Estacion Palytoxin-induced cell death cascade in bovine aortic endothelial cells Am J Physiol Cell Physiol, October 1, 2006; 291(4): C657 - C667. [Abstract] [Full Text] [PDF]

				D. Ferrari, C. Pizzirani, E. Adinolfi, R. M. Lemoli, A. Curti, M. Idzko, E. Panther, and F. Di Virgilio The P2X7 Receptor: A Key Player in IL-1 Processing and Release J. Immunol., April 1, 2006; 176(7): 3877 - 3883. [Abstract] [Full Text] [PDF]

				P. A. Verhoef, S. B. Kertesy, K. Lundberg, J. M. Kahlenberg, and G. R. Dubyak Inhibitory Effects of Chloride on the Activation of Caspase-1, IL-1{beta} Secretion, and Cytolysis by the P2X7 Receptor J. Immunol., December 1, 2005; 175(11): 7623 - 7634. [Abstract] [Full Text] [PDF]