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-1 betaand metalloproteinases

On direct cell-cell contact, stimulated T lymphocytes potently trigger the production of proinflammatory factors such as interleukin-1 beta (IL-1 beta ) and matrix metalloproteinases (MMP-1 and MMP-9), as well as anti-inflamma tory factors such as IL-1 receptor antagonist (IL-1Ra) and the tissue inhib itor of metalloproteinases (TIMP-1) in peripheral blood monocytes and the m onocytic cell line THP-1, Such mechanisms might play an important part in m any inflammatory diseases where tissue destruction occurs. To assess whethe r anti-inflammatory agents such as dexamethasone (DEX) and leflunomide (LF) would affect contact-activation of monocytic cells, T lymphocytes were sti mulated by PMA and PHA in the presence or absence of increasing concentrati ons of drug. LF and DEX (10(-4) M) inhibited the ability of stimulated T ly mphocytes to activate monocytic cells by 66-97% and 43-70%, respectively, d epending 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-1 beta and TI MP-1/MMP-1 produced by THP-1 cells was enhanced 3.6- and 1.9-fold, respecti vely, whereas it was enhanced only 1.3- and 1.4-fold upon contact with T ly mphocytes stimulated in the presence of 10(-4) M DEX. Therefore, LF tends t o favor the inhibition of pro-inflammatory and matrix-destructive factors o ver that of anti-inflammatory factors and metalloproteinase inhibitors, thu s interfering with both inflammation and tissue destruction, These experime nts indicate that LF and DEX have the potential to affect the capacity of s timulated T lymphocytes to activate, on direct cell-cell contact, monocytic cells. Furthermore, flow cytometric analysis revealed that surface molecul es of T lymphocytes that mere partially involved in contact-signaling of mo nocytes (i.e., CD69 and CD11) were not modulated by either LF or DEX, sugge sting that factors which remain to be identified were mainly involved in th e activation of monocytes on direct cell-cell contact.