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* Department of Pathology and Laboratory Medicine,
Department of Biochemistry, Microbiology, and Immunology, and
Division of Virology and Molecular Immunology, Research Institute, Children’s Hospital of Eastern Ontario, and
Ottawa Health Research Institute and the Division of Infectious Diseases, Department of Medicine, Ottawa Hospital General Campus, University of Ottawa, Ottawa, Ontario, Canada
The anti-inflammatory cytokine, IL-10 plays an important role in HIV immunopathogenesis. The HIV accessory protein, Tat is not only critical for viral replication, but affects the host immune system by influencing cytokine production including IL-10. During HIV infection, IL-10 production by monocytic cells is up-regulated, representing a critical pathway by which HIV may induce immunodeficiency. Herein, we show that extracellular Tat-induced IL-10 expression in normal human monocytes. To understand the signaling pathways underlying HIV-Tat induced IL-10 transcription, we investigated the involvement of MAPK as well as calcium signaling and the downstream transcription factor(s). Our results suggest that Tat-induced calcium influx regulated IL-10 transcription in monocytic cells. The experiments designed to further understand the molecules involved in the calcium signaling suggested that calmodulin and calmodulin-dependent protein kinase-II (CaMK-II)-activated p38 MAPK played a role in extracellular Tat-induced IL-10 expression in primary human monocytes. Furthermore, Tat-induced IL-10 expression was regulated by p38 MAPK- and CaMK II-activated CREB-1 as well as Sp-1 transcription factors. Taken together, our results suggest that extracellular HIV-Tat induced IL-10 transcription in primary human monocytes is regulated by CREB-1 and Sp-1 transcription factors through the activation of calmodulin/CaMK-II-dependent p38 MAPK.
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 This work was supported by grants from the Ontario HIV Treatment Network, and the Canadian Institute of Health Research (to A.K.). K.G. is supported by a fellowship from the Ontario HIV Treatment Network. S.M. was supported by a fellowship from the Ontario Graduate Scholarship program, and the Ontario Graduate Scholarships in Science and Technology program. A.K. and J.B.A. are recipients of the Career Scientist Award from the Ontario HIV Treatment Network.
2 Address correspondence and reprint requests to Dr. Ashok Kumar, Division of Virology, Department of Pathology and Laboratory Medicine, Research Institute, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada. E-mail address: akumar{at}uottawa.ca
3 Abbreviations used in this paper: CaM, calmodulin; CaMK, calmodulin kinase; ER, endoplasmic reticulum; IP3, inositol (1,4,5)-triphosphate; APB, aminoethoxydiphenyl borate; PKC, protein kinase C.
This article has been cited by other articles:
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  S. Gupta, R. Boppana, G. C. Mishra, B. Saha, and D. Mitra HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner J. Immunol., January 1, 2008; 180(1): 79 - 88. [Abstract] [Full Text] [PDF]
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