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First published online October 30, 2006
doi: 10.1242/10.1242/jcs.03206

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Host cell Ca²⁺ and protein kinase C regulate innate recognition of Toxoplasma gondii

¹ Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
² Department of Experimental Endocrinology, Medical University, Hanover, Germany
³ Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA

^* Author for correspondence (e-mail: chunter{at}vet.upenn.edu)

Accepted 8 August 2006

In healthy hosts, acute infection with the opportunistic pathogen Toxoplasma gondii is controlled by innate production of IL-12, a key cytokine crucial for the development of protective immunity. Previous work has established that the mitogen-activated protein kinases (MAPK), particularly p38 and ERK1/2, are important regulators of T. gondii-induced IL-12 synthesis. Here we report that host cell Ca²⁺ is required for activation of MAPK by T. gondii, as well as LPS and CpG, and for parasite-induced synthesis of IL-12. In addition, pharmacological mobilization of Ca²⁺ stores in macrophages treated with parasites or LPS enhanced MAPK phosphorylation initiated by these stimuli. Investigation of the upstream mechanism by which Ca²⁺ regulates MAPK activation revealed that T. gondii induced acute activation of conventional, Ca²⁺-dependent PKC and PKCß, which are required for infection-induced MAPK activation and production of IL-12. Despite these findings, neither acute parasite infection nor LPS initiated a measurable Ca²⁺ response in macrophages, suggesting that low levels of Ca²⁺ are permissive for initiation of pro-inflammatory signaling. Together these data identify host cell Ca²⁺ and PKC as crucial regulators of the innate immune response to microbial stimuli, including T. gondii.

Key words: Toxoplasma gondii, Interleukin 12, Mitogen-activated protein kinase, Ca²⁺, Macrophage/monocyte, Protein kinase C

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