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

• Published in: The Journal of immunology (1950) 2001-12, Vol.167 (12), p.6827-6833
• Main Authors: al-Ramadi, Basel K, Welte, Thomas, Fernandez-Cabezudo, Maria J, Galadari, Sehamuddin, Dittel, Bonnie, Fu, Xin-Yuan, Bothwell, Alfred L. M
• Format: Article
• Language: English
• Subjects: Animals; Clone Cells; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; I-kappa B Proteins; interleukin 1 receptors; Interleukin-1 - pharmacology; Kinetics; Lck protein; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - physiology; NF-kappa B - metabolism; NF-kappa B p50 Subunit; NF-KappaB Inhibitor alpha; Phosphorylation; Proto-Oncogene Proteins c-rel - metabolism; Receptors, Interleukin-1 - metabolism; Receptors, Interleukin-1 Type I; RNA, Antisense - pharmacology; Signal Transduction; Th2 Cells - immunology; Transcription Factor RelA
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.12.6827

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.