Eosinophils interact with nerve cells leading to changes in neurotransmitter release, altered nerve growth and protection from cytokine-induced apoptosis. In part these interactions occur as a result of activation of neural NF-B, which is activated by adhesion of eosinophils to neural intercellular adhesion molecule-1. The mechanism and consequence of signaling following eosinophil adhesion to nerve cells were investigated. Eosinophils membranes, which contain eosinophil adhesion molecules but not other eosinophil products, were co-incubated with IMR32 cholinergic nerve cells. The studies showed that there were two mechanisms of activation of NF-B, one of which was dependent on reactive oxygen species since it was inhibited with diphenyleneiodonium. This occurred at least 30 minutes after co-culture of eosinophils and nerves. An earlier phase of NF-B activation, occurred within 2 minutes of eosinophil adhesion and was mediated by tyrosine kinase dependent phosphorylation of IRAK-1. Co-immunoprecipitation experiments showed that both ERK1/2 and IRAK-1 were recruited to ICAM-1 rapidly after co-culture with eosinophil membranes. This was accompanied by an induction of ICAM-1, which was mediated by an IRAK-1 dependent pathway. These data indicate that adhesion of eosinophils to IMR32 nerves via ICAM-1 leads to important signaling events, mediated via IRAK-1 and these in turn lead to expression of adhesion molecules.