HIV and HIV Tat inhibit LPS-induced IL-23 production in human macrophages by distinct intracellular signaling pathways

Abstract

Abstract Monocyte-derived macrophages (MDMs) from HIV-infected patients and MDMs infected in vitro with HIV manifest inhibition of IL-12. Whether HIV infection or HIV accessory proteins such as tat, impact production of IL-23, a member of IL-12 family cytokines, in macrophages remains unknown. Our results show that in-vitro HIV infection, intracellular HIV-tat and HIV tat peptides inhibit LPS-induced IL-23 production in MDMs suggesting impairment of TLR-4 signalling. To study the mechanism governing HIV- and HIV-tat-mediated inhibition of LPS-induced IL-23 production, we first established that p38 mitogen-activated protein kinase (MAPK), the phosphoinositide-3-kinase (PI3K), and SRC homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1) positively regulated whereas c-Jun N-terminal kinase (JNK) MAPK negatively regulated LPS-induced IL-23 production in MDMs. HIV-Tat downregulated TNF-receptor associated factor (TRAF)-6 and inhibitor of apoptosis-1 (cIAP-1) and caused decreased phosphorylation of downstream PI3K, and p38 MAPKs. In contrast, HIV-tat-mediated inhibition of JNK MAPK negatively regulated IL-23 production. However, SHP-1 and Src kinases were not inhibited by HIV-Tat and hence were not implicated in tat-mediated inhibition of LPS-induced IL-23 production. In contrast to HIV-Tat, in vitro HIV infection of MDM inhibited LPS-induced IL-23 production via inhibition of p38 MAPK activation. Overall, HIV and HIV-Tat regulate LPS-induced IL-23 production in human macrophages via distinct mechanisms: HIV-Tat through the inhibition of cIAP-1-TRAF-6, and subsequent inhibition of PI3K and p38 and JNK MAPKs whereas HIV through the inhibition of p38 MAPK activation.