Paracrine Upregulation of Monocyte Cyclooxygenase-2 by Mediators Produced by T Lymphocytes: Role of Interleukin 17 and Interferon-g

LISA K. STAMP, MICHAEL J. JAMES, and LESLIE G. CLELAND

ABSTRACT.

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.

Conclusion. 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. (J Rheumatol 2004; 31: 1255-64)

Key Indexing Terms:

T CELLS
MONOCYTES
EICOSANOIDS
CYCLOOXYGENASE
INTERLEUKIN 17
INTERFERON-g

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From the Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia.

Supported by grants from The National Health and Medical Research Council of Australia and the Rose Hellaby Medical Research Scholarship to LKS.

L.K. Stamp, FRACP; M.J. James, PhD; L.G. Cleland, MD.

Address reprint requests to Prof. L. Cleland, Rheumatology Unit, Royal Adelaide Hospital, Adelaide SA 5000, Australia.

Submitted September 11, 2003; revision accepted January 15, 2004.

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