Lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatoryresponses upon binding to Toll-like receptor 4 (TLR4). One such anti-inflammatoryresponse is the increased production of interleukin-10 (IL-10), a cytokine thatnegatively regulates the activity of several transcription factors associated withinflammation. The expression of the tumour suppressor Programmed Cell Death 4 protein (Pdcd4) is key regulator in IL-10 production. Pdcd4 expression is regulated by multiple mechanisms in response to LPS, principally via
mRNAdegradation by MicroRNA-21 (miR-21) and phosphorylation by theAkt/mTOR/S6K1 pathway. However, the events downstream of Pdcd4 in this process are less well characterized. IL-10 mRNA contains a complex 5’ cap-structurewhich requires translation through the eIF4F complex. Pdcd4 suppresses protein production by binding eIF4A and inhibiting translation, but this interaction has not been shown in the context of LPS. Pdcd4 was seen to be degraded in response to LPSand this degradation was shown to be due to activation of mTOR. An interaction between Pdcd4 and eIF4a was also confirmed in transfected cells via co-immunoprecipitation, although the apparent stabilization of Pdcd4 conflicted with previous endogenous data. An interaction was also detected in an endogenous co-immunoprecipitation, and the pattern of Pdcd4 dissociation appeared to match that of the other endogenous experiments. The results suggest that IL-10 production inresponse to LPS may indeed be facilitated by the release of eIF4A by Pdcd4.