Disruption of MAP kinase activation and nuclear factor binding to the IL-12 p40 promoter in HIV-infected myeloid cells.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0057202 Publication Model: Print Cited Medium: Print ISSN: 0009-9104 (Print) Linking ISSN: 00099104 NLM ISO Abbreviation: Clin Exp Immunol Subsets: MEDLINE

Publication: 2022- : Oxford : Oxford University Press
Original Publication: Oxford : Blackwell Scientific Publications

HIV-1*; HIV Infections/*immunology ; Interleukin-12/*metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Myeloid Cells/*immunology ; Protein Subunits/*metabolism; Base Sequence ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Enzyme Activation/immunology ; Gene Expression Regulation ; HIV Infections/enzymology ; HIV Infections/genetics ; Humans ; Interleukin-12/genetics ; Interleukin-12 Subunit p40 ; Lipopolysaccharides/immunology ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Myeloid Cells/virology ; Promoter Regions, Genetic ; Protein Subunits/genetics ; Transcription Factors/metabolism ; Transcription, Genetic

Progressive immunodeficiency in HIV infection is paralleled by a decrease in IL-12 production, a cytokine crucial for cellular immune function. Here we examine the molecular mechanisms by which HIV infection suppresses IL-12 p40 expression. HIV infection of THP-1 myeloid cells resulted in decreased LPS-induced nuclear factor binding to the NF-kappaB, AP-1, and Sp1 sites of the IL-12 p40 promoter. By site-directed mutagenesis we determined that each of these sites was necessary for transcriptional activation of the IL-12 p40 promoter. Binding of NF-kappaB p50, c-Rel, p65, Sp1, Sp3, c-Fos, and c-Jun proteins to their cognate nuclear factor binding sites was somewhat impaired by HV infection, although a role for other as yet unidentified factors cannot be dismissed. The cellular levels of these transcription factors were unaffected by HIV infection, with the exception of a decrease in expression of NF-kappaB p65, consistent with the observed decrease in its binding to the IL-12 p40 promoter following HIV infection. Analysis of regulation of upstream LPS-induced MAP kinases demonstrated impaired phosphorylation of JNK and p38 MAPK, and suppressed phosphorylation and degradation of IkappaBalpha following HIV infection. These results suggest that alterations in nuclear factor binding to numerous sites in the IL-12 p40 promoter, together may contribute to the suppression in IL-12 p40 transcription previously reported. These effects on nuclear factor binding may be a direct effect of HIV infection on the IL-12 p40 promoter, or may occur indirectly as a consequence of altered MAP kinase activation.

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0 (DNA-Binding Proteins)
0 (Interleukin-12 Subunit p40)
0 (Lipopolysaccharides)
0 (Protein Subunits)
0 (Transcription Factors)
187348-17-0 (Interleukin-12)
EC 2.7.11.24 (Mitogen-Activated Protein Kinases)

Date Created: 20040724 Date Completed: 20040920 Latest Revision: 20181113

20250114

PMC1809123

10.1111/j.1365-2249.2004.02513.x

15270850