Glucocorticoid-mediated inhibition of Lck modulates the pattern of T cell receptor-induced calcium signals by down-regulating inositol 1,4,5-trisphosphate receptors.
Glucocorticoids are potent immunosuppressive agents that block upstream signaling events required for T cell receptor (TCR) activation. However, the mechanism by which glucocorticoids inhibit downstream responses, such as inositol 1,4,5-trisphosphate (IP(3))-induced calcium signals, is not completely understood. Here we demonstrate that low concentrations of dexamethasone rapidly convert transient calcium elevations to oscillations after strong TCR stimulation. Dexamethasone converted the pattern of calcium signaling by inhibiting the Src family kinase Lck, which was shown to interact with and positively regulate Type I IP(3) receptor. In addition, low concentrations of dexamethasone were sufficient to inhibit calcium oscillations and interleukin-2 mRNA after weak TCR stimulation. Together, these findings indicate that by inhibiting Lck and subsequently down-regulating IP(3) receptors, glucocorticoids suppress immune responses by weakening the strength of the TCR signal.
Division of Hematology and Oncology, Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Michael W
MW
Harr
Yiping
Y
Rong
Martin D
MD
Bootman
H Llewelyn
HL
Roderick
Clark W
CW
Distelhorst
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D047468:Immunoprecipitation; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013945:Thymoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013953:Thymus Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D003907:Dexamethasone; D015544:Inositol 1,4,5-Trisphosphate; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium