title: Interleukin-10 enhances human immunodeficiency virus type 1 expression in a chronically infected promonocytic cell line (U1) by a tumor necrosis factor alpha-independent mechanism.
abstract: TNF-alpha enhances HIV-1 replication in acutely and chronically infected cells and likely contributes to the wasting associated with the acquired immunodeficiency syndrome. Agents that inhibit TNF-alpha activity should theoretically delay the progression of disease, and several are currently in clinical trials. We hypothesized that IL-10, a cytokine that suppresses the gene expression and synthesis of TNF-alpha in monocytic cells, might inhibit HIV-1 replication. As expected, IL-10 suppressed PMA-induced TNF-alpha production in U1 cells; however, when U1 cells were cultured in the presence of PMA and increasing doses of IL-10, a dose-dependent increase in HIV-1 expression was observed. IL-10 also enhanced IL-1 beta-, TNF-alpha-, and GM-CSF-induced HIV-1 expression in U1 cells, and this occurred, at least in part, at the level of transcription. We next stimulated cells under conditions of TNF-alpha blockade. When PMA-induced TNF-alpha activity and HIV-1 replication were blocked by the presence of soluble TNF receptors, IL-10 independently enhanced HIV-1 replication. In contrast, other agents that are capable of blocking TNF-alpha synthesis or TNF-alpha activity either had no effect (IL-13 and IL-4) or inhibited HIV-1 expression (soluble TNF receptors and pentoxifylline) in U1 cells. These data suggest that IL-10, while inhibiting TNF-alpha synthesis, has an independent mechanism of action that enhances HIV-1 replication. Therefore, IL-10 may have undesirable effects in HIV-1-infected patients.
authors.affiliation: Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Angel
authors.forename: B M
authors.initials: BM
authors.lastname: Saget
authors.forename: M Z
authors.initials: MZ
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Wang
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: P R
authors.initials: PR
authors.lastname: Skolnik
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood*; D002460:Cell Line; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015497:HIV-1 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000821:virology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000821:virology; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate