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J Interferon Cytokine Res. 1998 Jul;18(7):499-507.

Increased inducible activation of NF-kappaB and responsive genes in astrocytes deficient in the protein tyrosine phosphatase SHP-1.

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  • 1The State University of New York, Health Science Center, Department of Neurology, Syracuse 13210, USA. massap@vax.cs.hscsyr.edu

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.

PMID:
9712366
DOI:
10.1089/jir.1998.18.499
[PubMed - indexed for MEDLINE]
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