To define the functional consequences of the src-homology domain-1 protein (SHP-1) defect, we examined cytokine production and NF-kappa B activity in motheaten viable (Mev) mice. We found elevated levels of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor (TNF), and interferon-gamma (IFN-gamma) in Mev mice sera and cultured B and T cells compared to littermate control adult mice. The levels of interleukin-2 (IL-2) detected in Mev sera and activated Mev T cells were decreased, but IL-2 receptor expression was increased. We then evaluated the activity of NF-kappa B and found that this protein is highly expressed in Mev B and T cells. To determine if NF-kappa B had a role in causing the elevated levels of cytokines in Mev mice, we treated activated Mev T cells with an NF-kappa B decoy and found that cell culture treatment with the decoy resulted in significant reduction of the secretion of IL-6, GM-CSF, and TNF, but not IFN-gamma. Therefore, our data show that Mev mice secrete elevated levels of inflammatory cytokines, which can be mediators in the development of the Mev clinical disorder, and that NF-kappa B has an important role in this process, impacting upon the regulation of the immune response.