title: Exposure of T lymphocytes to leflunomide but not to dexamethasone favors the production by monocytic cells of interleukin-1 receptor antagonist and the tissue-inhibitor of metalloproteinases-1 over that of interleukin-1beta and metalloproteinases.
abstract: On direct cell-cell contact, stimulated T lymphocytes potently trigger the production of pro-inflammatory factors such as interleukin-1beta (IL-1beta) and matrix metalloproteinases (MMP-1 and MMP-9), as well as anti-inflammatory factors such as IL-1 receptor antagonist (IL-1Ra) and the tissue inhibitor of metalloproteinases (TIMP-1) in peripheral blood monocytes and the monocytic cell line THP-1. Such mechanisms might play an important part in many inflammatory diseases where tissue destruction occurs. To assess whether anti-inflammatory agents such as dexamethasone (DEX) and leflunomide (LF) would affect contact-activation of monocytic cells, T lymphocytes were stimulated by PMA and PHA in the presence or absence of increasing concentrations of drug. LF and DEX (10- 4 M) inhibited the ability of stimulated T lymphocytes to activate monocytic cells by 66-97% and 43-70%, respectively, depending on the readout product. Upon contact with T lymphocytes stimulated in the presence of 10- 5 M LF, the molar ratio of IL-1Ra/IL-1beta and TIMP-1/MMP-1 produced by THP-1 cells was enhanced 3.6- and 1.9-fold, respectively, whereas it was enhanced only 1.3- and 1.4-fold upon contact with T lymphocytes stimulated in the presence of 10- 4 M DEX. Therefore, LF tends to favor the inhibition of pro-inflammatory and matrix-destructive factors over that of anti-inflammatory factors and metalloproteinase inhibitors, thus interfering with both inflammation and tissue destruction. These experiments indicate that LF and DEX have the potential to affect the capacity of stimulated T lymphocytes to activate, on direct cell-cell contact, monocytic cells. Furthermore, flow cytometric analysis revealed that surface molecules of T lymphocytes that were partially involved in contact-signaling of monocytes (i.e., CD69 and CD11) were not modulated by either LF or DEX, suggesting that factors which remain to be identified were mainly involved in the activation of monocytes on direct cell-cell contact.
authors.affiliation: Clinical Immunology Unit, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Tel: (+41) 22 372 93 76, Fax: (+41) 22 372 93 69.
authors.forename: V
authors.initials: V
authors.lastname: Déage
authors.forename: D
authors.initials: D
authors.lastname: Burger
authors.forename: J M
authors.initials: JM
authors.lastname: Dayer
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D008213:Lymphocyte Activation / Q000187:drug effects; D008666:Metalloendopeptidases / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology*; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; C507763:IL1RN protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007555:Isoxazoles; D012795:Sialoglycoproteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D003907:Dexamethasone; D008666:Metalloendopeptidases; D000077339:Leflunomide