Antibody-Dependent Enhancement Infection Facilitates Dengue Virus-Regulated Signaling of IL-10 Production in Monocytes

Interleukin (il)-10 levels are increased in dengue virus (denv)-infected patients with severe disorders. a hypothetical intrinsic pathway has been proposed for the il-10 response during antibody-dependent enhancement (ade) of denv infection; however,the mechanisms of il-10 regulation remain unclear.these results demonstrate that,in monocytes,il-10 production is regulated by ade through both an extrinsic and an intrinsic pathway,all involving a syk-regulated pi3k/pkb/gsk-3β/creb pathway,and both of which impact viral replication.we found that denv infection and/or attachment was sufficient to induce increased expression of il-10 and its downstream regulator suppressor of cytokine signaling 3 in human monocytic thp-1 cells and human peripheral blood monocytes. il-10 production was controlled by activation of cyclic adenosine monophosphate response element-binding (creb),primarily through protein kinase a (pka)- and phosphoinositide 3-kinase (pi3k)/pkb-regulated pathways,with pka activation acting upstream of pi3k/pkb. denv infection also caused glycogen synthase kinase (gsk)-3β inactivation in a pka/pi3k/pkb-regulated manner,and inhibition of gsk-3β significantly increased denv-induced il-10 production following creb activation. pharmacological inhibition of spleen tyrosine kinase (syk) activity significantly decreased denv-induced il-10 production,whereas silencing syk-associated c-type lectin domain family 5 member a caused a partial inhibition. ade of denv infection greatly increased il-10 expression by enhancing syk-regulated pi3k/pkb/gsk-3β/creb signaling. we also found that viral load,but not serotype,affected the il-10 response. finally,modulation of il-10 expression could affect denv replication. © 2014 tsai et al.