Induction of chemokine gene expression by major histocompatibility complex class II ligands in human fibroblast-like synoviocytes. Differential regulation by interleukin-4 and dexamethasone.
Chemokines play a key role in recruiting leukocytes into inflamed synovial environment, and the cells of the synovial membrane, which express high levels of major histocompatibility complex (MHC) class II molecules, are a major source of these chemokines. Our data indicated that engagement of MHC class II molecules by staphylococcal enterotoxin A superantigen resulted in the induction of chemokine gene expression as well as protein synthesis. Pretreatment of the cells with cycloheximide potentiated the effect of superantigen on chemokine mRNA induction, suggesting that the expression of these genes may occur independently of prior protein synthesis. Ligation of MHC class II molecules in fibroblast-like synoviocytes by other ligands such as Mycoplasma arthritidis-derived superantigen and anti-class II antibody could also trigger an increase in the mRNA level of RANTES, MCP-1, and interleukin (IL)-8. The addition of dexamethasone to superantigen-treated fibroblast-like synoviocytes inhibited the mRNA expression of all three chemokines. IL-4 treatment decreased only the stimulating effect of superantigen on RANTES messanger suggesting that different mechanisms are involved in regulating these genes. The inhibitory effect of dexamethasone did not require a de novo protein synthesis, whereas that of IL-4 was protein-dependent. This report demonstrates that MHC class II ligands (superantigens and anti-MHC class II antibodies) may represent an important agent by which inflammatory chemokines can be induced and shows that this response can be modulated by the anti-inflammatory agents dexamethasone and IL-4.
Mehindate
K
K
Centre de Recherche en Rhumatologie et Immunologie, CHUL, Université Laval, Ste. Foy, Québec, Canada.
al-Daccak
R
R
Schall
T J
TJ
Mourad
W
W
D002478:Cells, Cultured; D018946:Chemokine CCL5; D002630:Chemotactic Factors / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D004768:Enterotoxins / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics*; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018089:Superantigens / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D018946:Chemokine CCL5; D002630:Chemotactic Factors; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D016209:Interleukin-8; D008222:Lymphokines; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D018089:Superantigens; D015847:Interleukin-4; C026066:enterotoxin A, Staphylococcal; D003907:Dexamethasone