Increased Inducible Activation of NF-κB and Responsive Genes in Astrocytes Deficient in the Protein Tyrosine Phosphatase SHP-1

The protein tyrosine phosphatase SHP-1 is critical for controlling cytokine signaling through the Jak-Stat pathway and, consequently, for controlling inflammatory cellular immune responses dependent on these cytokines. However, the role of SHP-1 in regulating proinflammatory signaling may be incompletely understood, and it may control other distinct inflammatory agents. The present study analyzed the ability of tumor necrosis factor-α (TNF-α), double-stranded RNA, and interferon-γ (IFN-γ) to induce the transcription factor NFκB in astrocytes expressing or lacking SHP-1. On exposure to the inducers, NF-κB was markedly increased in astrocytes obtained from motheaten mice lacking SHP-1 compared with normal littermate cells expressing SHP-1, consisted of p50 and p65 subunits, and was induced in a protein synthesis-independent manner. The increased nuclear NF-κB expression coincided with elevated loss of the cytoplasmic inhibitor IκBα in motheaten mouse cells. Enhanced NF-κB expression in motheaten mouse cells correlated with increased expression of genes with functional κB sites, including IFN regulatory factor-1 (IRF-1) and inducible nitric oxide synthase (iNOS) genes. MHC class I molecules were also increased in motheaten cells, consistent with the increased expression of IRF-1. Together, the data indicate an increased sensitivity of cells lacking SHP-1 to various inducers of NF-κB. Therefore, the regulation of not only Stats but also of NF-κB by SHP-1 may be important in controlling events promoted by proinflammatory agents in vivo that are especially apparent in multiple tissues of motheaten mice. This study suggests an additional role for SHP-1 in controlling specific and nonspecific immune responses where induction of NF-κB is involved.