Addition of interleukin 1 (IL1) and IL17 soluble receptors to a tumour necrosis factor alpha soluble receptor more effectively reduces the production of IL6 and macrophage inhibitory protein-3alpha and increases that of collagen in an in vitro model of rheumatoid synoviocyte activation.
OBJECTIVE
To evaluate the usefulness of combination treatment with cytokine inhibitors.


METHODS
A simplified model was set up to evaluate the effect of tumour necrosis factor alpha (TNFalpha) soluble receptors (sTNFR) used alone and in combination with soluble interleukin 1 receptor (sIL1R) and sIL17R on the production of markers of inflammation (IL6), of migration of dendritic cells (macrophage inhibitory protein-3alpha (MIP-3alpha)), and of matrix synthesis (C-propeptide of type 1 collagen (P1CP)). Synoviocytes were stimulated with supernatants of activated peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA). Soluble receptors (sR) were preincubated at 1 gammag/ml alone or in combination with the supernatants before addition to RA synoviocytes. IL6, MIP-3alpha, and P1CP production was measured by enzyme linked immunosorbent assay (ELISA) in 48 hour synoviocyte supernatants.


RESULTS
IL6 production decreased by 16% with sTNFR alone compared with no sTNFR (p<0.001) and by 41% with the combination of the three sR (p<0.001). MIP-3alpha production decreased by 77% with sTNFR alone compared with no sTNFR (p<0.001) and by 98% with the combination of the three sR (p<0.001). In the presence of sTNFR alone, P1CP production increased by 25% compared with no sR (p<0.01). The combination of the three sR increased P1CP production by 48% (p<0.01).


CONCLUSIONS
The effect of sTNFR on IL6, MIP-3alpha, and P1CP production by RA synoviocytes stimulated by activated PBMC supernatants was further enhanced when combined with sIL1R and sIL17R.
Department of Immunology, Hôpital E Herriot, 69437 Lyon Cedex 03, France.
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Chevrel
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Garnero
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Miossec
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000378:metabolism*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology*; D013583:Synovial Membrane / Q000378:metabolism
D015415:Biomarkers; C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; C109985:IL17RA protein, human; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053722:Receptors, Interleukin-17; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins