Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN.
Although glucocorticoid (GC)-induced nongenomic effects have been reported, the underlying mechanisms remain unexplained. We previously described that lymphocyte-specific protein tyrosine kinase (LCK) and FYN oncogene related to SRC, FGR, YES (FYN) mediate GC-induced inhibition of T-cell-receptor (TCR) signalling. Here we characterize the underlying molecular mechanism. The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. Experiments with cells transfected with GC-receptor short interfering RNA (siRNA) showed that the GC receptor is an essential component of the TCR signalling complex. Short-term GC treatment induces dissociation of this protein complex, resulting in impaired TCR signalling as a consequence of abrogated LCK/FYN activation. HSP90siRNA-transfected cells are not able to assemble this TCR-associated multiprotein complex, and accordingly HSP90siRNA treatment mimics GC effects on LCK/FYN activities. These observations support a model for nongenomic GC-induced immunosuppression on the basis of dissolution of membrane-bound GC-receptor multiprotein complexes after GC-receptor ligation.
Löwenberg
Mark
M
Laboratory of Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. m.lowenberg@amc.uva.nl
Verhaar
Auke P
AP
Bilderbeek
Joyce
J
Marle
Jan van
Jv
Buttgereit
Frank
F
Peppelenbosch
Maikel P
MP
van Deventer
Sander J
SJ
Hommes
Daniel W
DW
D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000187:drug effects*; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
D015704:CD4 Antigens; D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn