Functional consequences of the SHP-1 defect in motheaten viable mice: role of NF-kappa B.
To define the functional consequences of the src-homology domain-1 protein (SHP-1) defect, we examined cytokine production and NF-kappa B activity in motheaten viable (Mev) mice. We found elevated levels of interleukin-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 interleukin-2 (IL-2) detected in Mev sera and activated Mev T cells were decreased, but IL-2 receptor expression was increased. We then evaluated the activity of NF-kappa B and found that this protein is highly expressed 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 activated Mev T cells with an NF-kappa B decoy and found that cell culture treatment with the decoy resulted in significant reduction of the secretion 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 disorder, and that NF-kappa B has an important role in this process, impacting upon the regulation of the immune response.
Khaled
A R
AR
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville 32610, USA.
Butfiloski
E J
EJ
Sobel
E S
ES
Schiffenbauer
J
J
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; 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; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases