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J. Biol. Chem., Vol. 282, Issue 18, 13351-13362, May 4, 2007

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Cyclosporin A and FK506 Inhibit IL-12p40 Production through the Calmodulin/Calmodulin-dependent Protein Kinase-activated Phosphoinositide 3-Kinase in Lipopolysaccharide-stimulated Human Monocytic Cells^*

Wei Ma¹², Sasmita Mishra¹³, Katrina Gee^¶4, Jyoti P. Mishra³, Devki Nandan^||, Neil E. Reiner^||, Jonathan B. Angel⁵, and Ashok Kumar^¶**6

From the Departments of ^**Pathology and Laboratory Medicine, and Biochemistry, Microbiology and Immunology, ^¶Division of Virology and Molecular Immunology, Research Institute, Children's Hospital of Eastern Ontario, Ottawa Health Research Institute and the Division of Infectious Diseases, Ottawa Hospital General Campus, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada and the ^||Division of Infectious Diseases, Departments of Medicine, and Microbiology and Immunology, University of British Columbia, Faculties of Medicine and Science, and Vancouver Coastal Health Research Institute, Vancouver, V5Z 3J5 British Columbia, Canada

Cyclosporine-A (CyA) and FK506 are potent immunosuppressive agents because of their ability to suppress the production of Th1 cytokines including interleukin (IL)-12. However, the mechanisms underlying the inhibitory effects of CyA and FK506 on the production of IL-12p40, a critical component of IL-12, remain unknown. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signaling pathway. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signaling pathways have been shown to negatively regulate lipopolysaccharide (LPS)-induced murine IL-12p40 production. Contrary to these observations, we show that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by the calcium pathway and in particular by calmodulin-(CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS-induced IL-12p40 production was regulated by the p110 catalytic subunit of PI3K. Moreover, LPS induced IL-12p40 production through the CaM/CaMK-II-activated NFB and AP-1 transcription factors. LPS-induced IL-12p40 production is known to be regulated by the c-Jun N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 down-regulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NFB and AP-1 independent of the JNK pathway.

Received for publication, December 15, 2006 , and in revised form, February 26, 2007.

^* This work was supported by grants from the Canadian Institute of Health Research (to A. K. and N. E. R. (MOP-8633)) and by Michael Smith Foundation for Health Research Research Unit Infrastructure Grant RUA042031 (to N. E. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this manuscript.

² Supported by a fellowship from the Natural Sciences and Engineering Research Council, Canada.

³ Both authors were supported by fellowships from the Ontario Graduate Scholarship program and the Ontario Graduate Scholarships in Science and Technology program.

⁴ Supported by a fellowship from the Ontario HIV Treatment Networks (OHTN).

⁵ Recipient of a Career Scientist Award from the OHTN.

⁶ Recipient of a Career Scientist Award from the OHTN. To whom correspondence should be addressed: Division of Virology, Dept. of Pathology and Laboratory Medicine, Research Institute, Children's Hospital of Eastern Ontario, 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada. Tel.: 613-737-7600 (ext. 3920); Fax: 613-738-4825; E-mail: akumar{at}uottawa.ca.

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