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The Journal of Immunology, 2001, 167: 6827-6833.
Copyright © 2001 by The American Association of Immunologists

The Src-Protein Tyrosine Kinase Lck Is Required for IL-1-Mediated Costimulatory Signaling in Th2 Cells1

Basel K. al-Ramadi2,*, Thomas Welte§, Maria J. Fernandez-Cabezudo*, Sehamuddin Galadari{dagger}, Bonnie Dittel3,{ddagger}, Xin-Yuan Fu§ and Alfred L. M. Bothwell{ddagger}

Departments of * Medical Microbiology and {dagger} Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; and {ddagger} Section of Immunobiology and § Department of Pathology, Yale University School of Medicine, New Haven, CT 06510

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-{kappa}B 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 I{kappa}B-{alpha} and an incomplete activation of NF-{kappa}B heterodimeric complexes. Protein expression of NF-{kappa}B 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.




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