First Author | Mehta HV | Year | 2012 |
Journal | J Immunol | Volume | 189 |
Issue | 8 | Pages | 4088-103 |
PubMed ID | 22972924 | Mgi Jnum | J:190518 |
Mgi Id | MGI:5449081 | Doi | 10.4049/jimmunol.1200777 |
Citation | Mehta HV, et al. (2012) IFN-alpha and lipopolysaccharide upregulate APOBEC3 mRNA through different signaling pathways. J Immunol 189(8):4088-103 |
abstractText | APOBEC3 (A3) proteins are virus-restriction factors that provide intrinsic immunity against infections by viruses like HIV-1 and mouse mammary tumor virus. A3 proteins are inducible by inflammatory stimuli, such as LPS and IFN-alpha, via mechanisms that are not fully defined. Using genetic and pharmacological studies on C57BL/6 mice and cells, we show that IFN-alpha and LPS induce A3 via different pathways, independently of each other. IFN-alpha positively regulates mouse APOBEC3 (mA3) mRNA expression through IFN-alphaR/PKC/STAT1 and negatively regulates mA3 mRNA expression via IFN-alphaR/MAPKs-signaling pathways. Interestingly, LPS shows some variation in its regulatory behavior. Although LPS-mediated positive regulation of mA3 mRNA occurs through TLR4/TRIF/IRF3/PKC, it negatively modulates mA3 mRNA via TLR4/MyD88/MAPK-signaling pathways. Additional studies on human peripheral blood mononuclear cells reveal that PKC differentially regulates IFN-alpha and LPS induction of human A3A, A3F, and A3G mRNA expression. In summary, we identified important signaling targets downstream of IFN-alphaR and TLR4 that mediate A3 mRNA induction by both LPS and IFN-alpha. Our results provide new insights into the signaling targets that could be manipulated to enhance the intracellular store of A3 and potentially enhance A3 antiviral function in the host. |