EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption

Enteropathogenic Escherichia coli (EPEC) alters many functions of the host intestinal epithelia. Inflammation is initiated by activation of nuclear fa ctor (NF)-kappaB, and paracellular permeability is enhanced via a Ca2+- and myosin light-chain kinase (MLCK)-dependent pathway. The aims of this study were to identify signaling pathways by which EPEC triggers inflammation an d to determine whether these pathways parallel or diverge from those that a lter permeability. EPEC-induced phosphorylation and degradation of the prim ary inhibitor of NF-kappaB (I kappaB alpha) were tumor necrosis factor (TNF )-alpha and interleukin (IL)-1 beta independent. In contrast to Salmonella typhimurium, EPEC-stimulated I kappaB alpha degradation and IL-8 expression did not require Ca2+. Instead, extracellular signal-regulated kinase (ERK) -1/2 was significantly and rapidly activated. ERK1/2 inhibitors attenuated I kappaB alpha degradation and IL-8 expression. Although ERK1/2 can activat e MLCK, its inhibition had no impact on EPEC disruption of the tight juncti on barrier. In conclusion, EPEC-induced inflammation 1) is TNF-alpha and IL -1 beta receptor independent, 2) utilizes pathways differently from S. typh imurium, 3) requires ERK1/2, and 4) employs signals that are distinct from those that alter permeability. This is the first time that EPEC-activated s ignaling cascades have been linked to independent functional consequences.