Abstract:
: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.
journal_name
Clin Exp Immunoljournal_title
Clinical and experimental immunologyauthors
Chambers KA,Parks RJ,Angel JBdoi
10.1111/j.1365-2249.2004.02513.xsubject
Has Abstractpub_date
2004-08-01 00:00:00pages
329-40issue
2eissn
0009-9104issn
1365-2249pii
CEI2513journal_volume
137pub_type
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
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journal_title:Clinical and experimental immunology
pub_type: 杂志文章
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doi:
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journal_title:Clinical and experimental immunology
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