title: HIV-1 Nef inhibits lipopolysaccharide-induced IL-12p40 expression by inhibiting JNK-activated NFkappaB in human monocytic cells.
abstract: Impaired cellular immunity caused by decreased production of Th1-type cytokines, including interleukin-12 (IL-12) is a major feature of HIV-1-associated immunodeficiency and acquired immunodeficiency syndrome. IL-12p40, an inducible subunit shared between IL-12 and IL-23, plays a critical role in the development of cellular immunity, and its production is significantly decreased during HIV infection. The mechanism by which HIV induces loss of IL-12p40 production remains poorly understood. We have previously shown that lipopolysaccharide (LPS)-induced IL-12p40 production in monocytic cells is regulated by NFkappaB and AP-1 transcription factors through the activation of two distinct upstream signaling pathways, namely the c-Jun-N-terminal kinase (JNK) and the calmodulin-dependent protein kinase-II-activated pathways. Herein, we show that intracellular nef expressed through transduction of primary monocytes and promonocytic THP-1 cells with retroviral-mediated nef gene inhibited LPS-induced IL-12p40 transcription by inhibiting the JNK mitogen-activated protein kinases without affecting the calmodulin-dependent protein kinase-II-activated pathway. In addition, nef inhibited JNK-activated NFkappaB without affecting the AP-1 activity. Overall, our results suggest for the first time that intracellular nef inhibited LPS-activated JNK, which may cause inhibition of IL-12p40 expression in human monocytic cells by selectively inhibiting NFkappaB activity.
authors.affiliation: Department of Pathology , Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.forename: Sasmita
authors.initials: S
authors.lastname: Mishra
authors.forename: Niranjala
authors.initials: N
authors.lastname: Gajanayaka
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Angel
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*
chemical_list: C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048670:MAP Kinase Kinase 4