Since apoptosis is a key mechanism that limits viral replication, it might have been expected that endogenous TGF-b would dampen RV1B replication. However, we could find no effect of anti TGF-b antibodies on caspase activation and RV1B replication was consistently decreased in the presence of anti TGF-b antibodies. These findings contrast with studies of RSV infection which have reported that exogenous TGF-b1 is beneficial for RSV replication via mechanisms that involved cell cycle arrest. Of interest, RSV infection also augmented TGF-b production by infected epithelial cells, although in our own studies, we could find no evidence of increased TGF-b isoform mRNA expression following RV infection. Instead, our data suggested that rather than containing virus infection by inducing apoptosis, the presence of high endogenous level of this cytokine promoted virus replication by suppressing the innate immune response. In addition to its role in regulating the cell cycle, TGF-b also plays a role in the control of innate and adaptive immunity. Thus, TGF-b plays a role in promotion of Th17 lineage commitment and has been implicated in the initial amplification of the innate immune response through recruitment of monocytes and neutrophils. It also has important anti-inflammatory roles including coordination of regulatory T cell development and function including suppression of Th1 and Th2 cell development. While the responses to TGF-b are closely regulated by environmental stimuli and the accompanying cytokine milieu, the extremely pleiotropic nature of this cytokine has led to the suggestion. In our experiments, we observed that endogenous TGF-b acts more like an anti-inflammatory cytokine as treatment with LY2109761 neutralizing antibodies promoted induction of both type I and type III interferon responses to either virus infection or the synthetic dsRNA, poly IC. This observation is the first report that TGFb can directly affect expression of Type III interferon and extends previous studies in bronchial fibroblasts where the authors found a dampening of IFN-b expression following rhinovirus infection in the presence of TGF-b1. However, in the latter case, the authors reported that the effect of TGF-b1 appeared to be rapid and mediated via effects on IFN regulatory factor -3 pathways. In contrast, in our studies with PBECs, the effect of TGF-b was slow and appeared to involve members of the SOCS family of suppressors of cytokine signaling as evidenced by decreased SOCS-1 and SOCS-3 gene expression when we blocked endogenous TGF-b. SOCS-1 and SOCS-3 do not interfere with direct TLR signaling, but avoid overshooting activation by regulating IFN-b signaling and both have been shown to be induced by TGF-b. Using siRNA targeting SOCS-3, we were able to significantly knockdown SOCS-3 expression and found a trend for increased IFN-b release when epithelial cells were treated with poly IC in the presence of TGF-b. However, as we were unable to significantly knock down SOCS-1 using the same approach, we were unable to test the cumulative effect of attenuating the inhibitory effects of both suppressor proteins. Thus, while further work is still required to demonstrate causality between SOCS-1 and modulation of the IFN response, the slow kinetics of the anti TGF-b effect on viral replication are more consistent with a slow, cumulative effect of TGF-b involving increased SOCS expression and suppression.