Paracrine upregulation of monocyte cyclooxygenase-2 by mediators produced by T lymphocytes: role of interleukin 17 and interferon-gamma.
OBJECTIVE
Cyclooxygenase (COX)-2 is an inducible eicosanoid-forming enzyme that is expressed at sites of inflammation. T lymphocytes and monocytes are found in close proximity at sites of inflammation, including synovitis. We investigated whether activated T lymphocytes express COX-2 and whether activated T cells upregulate monocyte COX-2 expression.


METHODS
Human T lymphocytes and monocytes were isolated from fresh buffy coats by density gradient separation followed by passage through either nylon wool columns (T lymphocytes) or counter-current elutriation (monocytes). T lymphocytes were stimulated using anti-CD3 and anti-CD28 in a co-culture system with monocytes using transwells, which prevents cell-cell contact, but allows diffusion of soluble mediators.


RESULTS
Repeated examination of COX isotypes in resting and stimulated T cells revealed COX-1, but not COX-2. Activated T cells produced a soluble mediator(s) that upregulated monocyte COX-2. Mediator production was inhibited by cyclosporin A. Activated T cells produced interleukin 17 (IL-17) and interferon-g (IFN-g), and in the co-culture IL-17-neutralizing antibodies partially reduced monocyte COX-2 expression, whereas IFN-g-neutralizing antibodies had the opposite effect. Exogenous IL-17 upregulated monocyte COX-2, although concentrations were high compared with those generated by stimulated T cells. By contrast, monocyte COX-2 expression was downregulated when monocytes were treated with IFN-g prior to stimulation with lipopolysaccharide.


CONCLUSIONS
Soluble mediators produced by activated T cells can influence induction of monocyte COX-2, with IL-17 acting as a positive paracrine regulator and IFN-g acting as a negative regulator. In rheumatoid joints, previously observed high concentrations of IL-17 and low concentrations of IFN-g could contribute to T cell-driven upregulation of monocyte COX-2.
Stamp
Lisa K
LK
Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000, Australia.
James
Michael J
MJ
Cleland
Leslie G
LG
D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015777:Eicosanoids / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins; D009000:Monocytes / Q000276:immunology*; D019899:Paracrine Communication / Q000276:immunology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D015777:Eicosanoids; D018836:Inflammation Mediators; D020381:Interleukin-17; D007527:Isoenzymes; D008565:Membrane Proteins; D007371:Interferon-gamma; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases