FUNCTIONAL CONSEQUENCES OF THE SHP-1 DEFECT IN MOTH-EATEN VIABLE MICE- ROLE OF NF-KAPPA-B

To define the functional consequences of the src-homology domain-1 pro tein (SHP-1) defect, we examined cytokine production and NF-kappa B ac tivity in motheaten viable (Mev) mice. We found elevated levels of int erleukin-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 inte rleukin-a (IL-2) detected in Mev sera and activated Mev T cells were d ecreased, but IL-2 receptor expression was increased. We then evaluate d the activity of NF-kappa B and found that this protein is highly exp ressed 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 activ ated Mev T cells with an NF-kappa B decoy and found that cell culture treatment with the decoy resulted in significant reduction of the secr etion 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 disorde r, and that NF-kappa B has an important role in this process, impactin g upon the regulation of the immune response. (C) 1998 Academic Press.