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

Abstract

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-alpha (TNF-alpha), double-stranded RNA, and interferon-gamma (IFN-gamma) to induce the transcription factor NF-kappaB in astrocytes expressing or lacking SHP-1. On exposure to the inducers, NF-kappaB 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-kappaB expression coincided with elevated loss of the cytoplasmic inhibitor IkappaB alpha in motheaten mouse cells. Enhanced NF-kappaB expression in motheaten mouse cells correlated with increased expression of genes with functional kappaB 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-kappaB. Therefore, the regulation of not only Stats but also of NF-kappaB 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-kappaB is involved.

RNA-Dependent Protein Kinase PKR Is Required for Activation of NF-κB by IFN-γ in a STAT1-Independent Pathway

“…Therefore, the regulation of not only Stats, but also NF-B, by SHP-1 is important in controlling events promoted by proinflammatory agents in vivo. It further emphasizes an additional role for SHP-1 in controlling specific and nonspecific immune responses where induction of NF-B is involved (43). It is interesting to note that PKR mediates activation of NF-B by TNF-␣ and dsRNA (18,19), and in this study we show that IFN-␥ also signals through PKR to activate the same transcription factor to regulate IRF-1.…”

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

“…Interplay between SHP-1 and NF-kB pathways has previously been reported in B and T cells and astrocytes, and is consistent with a dysregulation of NF-kB observed in mutant motheaten mice that express a catalytically inactive form of SHP-1. 33,34 However, molecular mechanisms for this regulation have not been described yet. Our findings demonstrate that sst2 regulates NF-kB through the phosphorylation and the degradation of its inhibitor IkBa.…”

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

“…In particular, evidence has been provided that NO released under basal conditions by cNOS keeps iNOS under a nonactivated state through the inhibition of the NF-B signaling, which in turn regulates the iNOS transcriptional mechanisms. In particular, it is known that NF-B represents one of the most relevant signaling pathways that mediates the expression of iNOS following many extracellular mediators, including endotoxin and inflammatory cytokines (Bonaiuto et al, 1997;Chao et al, 1997;Massa and Wu, 1998;HartlageRubsamen et al, 1999). When low concentration of endogenous as well as exogenous NO is released, NF-B is kept in an inactive state (Togashi et al, 1997).…”