Increased inducible activation of NF-kappaB 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-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.
The State University of New York, Health Science Center, Department of Neurology, Syracuse 13210, USA. massap@vax.cs.hscsyr.edu
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D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011500:Protein Synthesis Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D003513:Cycloheximide; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse