Lactic acid delays the inflammatory response of XXXX monocytes.

@entity1 @entity558 @entity5 @entity310 @entity4284 @entity584 @entity7721 @entity2842 @entity880 @entity19794 @entity4452
UNASSIGNED: @entity880 (LA) accumulates under inflammatory conditions, e.g. in wounds or @entity5 , and influences local immune cell functions. We previously noted inhibitory effects of LA on glycolysis and @entity310 secretion of @entity1 @entity558 -stimulated monocytes. Here, we globally analyze the influence of LA on gene expression during monocyte activation. To separate LA-specific from @entity880 - or pH-effects, monocytes were treated for one or four hours with @entity558 in the presence of physiological concentrations of LA, @entity19794 (NaL) or acidic pH. Analyses of global gene expression profiles revealed striking effects of LA during the early stimulation phase. Up-regulation of most @entity558 -induced genes was significantly delayed in the presence of LA, while this inhibitory effect was attenuated in acidified samples and not detected after incubation with NaL. LA targets included genes encoding for important monocyte effector proteins like cytokines (e.g. @entity310 and @entity4452 ) or chemokines (e.g. @entity2842 and @entity7721 ). LA effects were validated for several targets by quantitative RT-PCR and/or ELISA. Further analysis of @entity558 -signaling pathways revealed that LA delayed the phosphorylation of protein kinase B ( @entity584 ) as well as the degradation of @entity4284 . Consistently, the @entity558 -induced nuclear accumulation of NFkB was also diminished in response to LA. These results indicate that the broad effect of LA on gene expression and function of @entity1 monocytes is at least partially caused by its interference with immediate signal transduction events after activation. This mechanism might contribute to monocyte suppression in the @entity5 environment.
