Natural Killer-22 Cells in the Synovial Fluid of Patients with Rheumatoid Arthritis Are an Innate Source of Interleukin 22 and Tumor Necrosis Factor-α

Objective. To determine the role of natural killer (NK)-22 cells in the pathogenesis of rheumatoid arthritis (RA). Methods. Using flow cytometry, the proportions of NK-22 cells and intracellular contents of perforin, granzyme B, and interferon-gamma (IFN-gamma) were determined in the peripheral blood (PB) and synovial fluid (SF) of patients with RA and healthy individuals. The levels of interleukin 22 (IL-22) and tumor necrosis factor-alpha (TNF-alpha) in the NK-22 supernatant and gene expressions were measured using ELISA and QuantiGene Plex assay, respectively. The effect of NK-22 supernatant on the proliferation of fibroblast-like synoviocytes (FLS) and recombinant human IL-22 (rhIL-22) on the production of monocyte chemoattractant protein 1 (MCP-1) by RA FLS was detected using the yellow tetrazolium salt method and ELISA, respectively. The relationship between the proportions of NK-22 cells and disease activity was analyzed. Results. NKp44 and CCR6 were expressed in a larger population of SF NK cells than in the PB NK cells of patients with RA. NK-22 cells produce low content of perforin, granzyme B, and IFN-gamma. NK-22 cells in vitro can secrete IL-22 and TNF-alpha and there was increased messenger RNA coding for IL-22 and TNF-alpha. NK-22 supernatant can induce the proliferation of RA FLS. Addition of IL-22 antibody plus TNF-alpha antibody inhibited the proliferation of FLS induced by the NK-22 supernatant. Both rhIL-22 1 ng/ml and rhIL-22 10 ng/ml induced the production of MCP-1 by RA FLS. The NK-22 proportions were positively correlated with disease activity. Conclusion. NK-22 cells are increased in patients with RA and might play a role in the pathogenesis of RA through the production of IL-22 and TNF-alpha. The proportion of NK-22 cells and disease activity were highly correlated. (First Release July 15 2011; J Rheumatol 2011;38:2112-18; doi:10.3899/jrheum.101377)