treatment with tnfalpha and ifngamma alters the activation of serthr protein kinases and the metabolic response to igfi in mouse c2c12 myogenic cells unlabelled the aim of this study was to compare the effects of tnfalpha il1beta and ifngamma on the activation of protein kinase b pkb p70s6k mitogenactivated protein kinase mapk and p90 rsk and on igfistimulated glucose uptake and protein synthesis in mouse c2c12 myotubes 100 nmoll igfi stimulated glucose uptake in c2c12 myotubes by 1981 and 10 ngml tnfalpha abolished this effect glucose uptake in cells differentiated in the presence of 10 ngml ifngamma increased by 1672 but did not undergo significant further modification upon the addition of igfi igfi increased the rate of protein synthesis by 2498 neither tnfalpha nor ifngamma influenced basal protein synthesis but both cytokines prevented the igfi effect 10 ngml il1beta did not modify either the basal or igfidependent glucose uptake and protein synthesis with the exception of tnfalpha causing an 18 decrease in the level of pkb protein the cellular levels of pkb p70s6k p42mapk p44mapk and p90 rsk were not affected by the cytokines igfi caused the phosphorylation of pkb an approximate 8fold increase above the basal value after 40 min of igfi treatment p42mapk a 281fold increase after 50 min and the activation of p70s6k and p90 rsk manifesting as gel mobility retardation in cells differentiated in the presence of tnfalpha or ifngamma this igfimediated pkb and p70s6k phosphorylation was significantly diminished and the increase in p42mapk and p90 rsk phosphorylation was prevented the basal p42mapk phosphorylation in c2c12 cells treated with ifngamma was high and comparable with the activation of this kinase by igfi pretreatment of myogenic cells with il1beta did not modify the igfistimulated phosphorylation of pkb p70s6k p42mapk and p90 rsk in conclusion i tnfalpha and ifngamma but not il1beta if present in the extracellular environment during c2c12 myoblast differentiation prevent the stimulatory action of igfi on protein synthesis ii tnfalpha and ifngammainduced igfi resistance of protein synthesis could be associated with the decreased phosphorylation of pkb and p70s6k iii the activation of glucose uptake in c2c12 myogenic cells treated with ifngamma is pkb independent iv the similar effects of tnfalpha and ifngamma on the signalling and action of igfi on protein synthesis in myogenic cells could suggest the involvement of both of these cytokines in protein loss in skeletal muscle