Orthopox viruses, including the vaccinia virus, produce proteins that mimic cytokine receptors, such as those for IFN-α, IFN-β, IFN-γ, IL-1β, IL-18, and TNFα, and disturb the cytokine signal transduction system. Other viral proteins also disturb the intracellular signal transduction systems. The viral A46R protein has a TIR domain, and interacts with MyD88 and TRIF, suppressing both IL-1 and TLR signal transduction, but not TNF-α signal transduction [49] . The viral A52R protein binds to IRAK2, suppresses TRAF6-dependent IKK and NF-κB activation, and then inhibits production of IL-8 and RANTES. However, A52R also binds to TRAF6 and promotes polyubiquitination of TRAF6, TAK1 activation, MAPKK6 phosphorylation, and activation of the JNK-p38 MAP kinase pathway. The later leads to the induction of IL-10 production [50] . The viral N1L protein interacts with the IKK complex (IKKα-IKKβ-IKKγ), TBK1, and IKKε, and then suppresses the activation of NF-κB and IRF-3 [51] . Vaccinia virus not only suppresses proinflammatory cytokines, but also induces production of an immunosuppressive cytokine IL-10, which shifts the Th1 response and suppresses cellular immunity. Human monocytes infected with vaccinia virus produce IL-10, and this IL-10 is then further upregulated by stimulation with LPS [52] .