The Src-protein tyrosine kinase Lck is required for IL-1-mediated costimulatory signaling in Th2 cells.
Src-protein tyrosine kinases are intimately involved in TCR-initiated signaling in T lymphocytes. One member of this family, Lck, is also involved in CD28-mediated costimulation in Th1 cells. In Th2 lymphocytes, the costimulatory signal can also be provided by the interaction of IL-1 with type I IL-1R (IL-1RI), culminating in the activation of NF-kappaB transcription factors. Proximal steps in the IL-1R pathway, however, remain poorly understood, and there is conflicting evidence as to the importance of tyrosine phosphorylation in IL-1R signaling. We have addressed this issue by examining the ability of IL-1 to costimulate the activation of Lck-deficient Th2 cells. Our data demonstrate that, in the absence of Lck, the IL-1 costimulatory pathway is blocked despite the expression of normal levels of IL-1RI. Moreover, the block is associated with a defective degradation of IkappaB-alpha and an incomplete activation of NF-kappaB heterodimeric complexes. Protein expression of NF-kappaB monomers, including p50, p65, and c-Rel, is equivalent in both wild-type and Lck-deficient Th2 cell clones. Finally, we demonstrate that, in normal Th2 cells, stimulation with IL-1 leads to a rapid induction in tyrosine phosphorylation of several substrates including Lck itself. These findings strongly suggest that Lck is required for signaling in the IL-1 costimulatory pathway in Th2 lymphocytes.
al-Ramadi
B K
BK
Department of Medical Microbiology and Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. ramadi.b@uaeu.ac.ae
Welte
T
T
Fernandez-Cabezudo
M J
MJ
Galadari
S
S
Dittel
B
B
Fu
X Y
XY
Bothwell
A L
AL
D000818:Animals; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D010766:Phosphorylation; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D016372:RNA, Antisense / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*; D051996:Transcription Factor RelA
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D016372:RNA, Antisense; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)