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The biologic response to particulate load after arthroplasty has not been fully characterized but is believed mediated by proinflammatory cytokines released from mononuclear cells in the periprosthetic region. To investigate the contribution of lymphocytes to expression of proinflammatory genes induced by metal particles, we compared gene expression of mononuclear cells in response to metal and polymethylmethacrylate particles using cDNA microarray profiling. Peripheral blood mononuclear cells and monocytes were stimulated with polymethylmethacrylate and titanium particles of clinically relevant sizes. Polymethylmethacrylate elicited a six- to 12-fold increase in gene expression of tumor necrosis factor alpha, interleukin 1a, interleukin 1p, interleukin 6, and in-terleukin 8 in purified monocytes and unfractionated peripheral blood mononuclear cells. Although the effect of titanium on stimulation of purified monocytes was modest, stimulation of lymphocyte-containing peripheral blood mononuclear cells by titanium particles resulted in monocyte-derived proinflammatory cytokine expression. In contrast to polymethylmethacrylate, titanium particles stimulated increased expression of T lymphocyte-derived cytokines, including interleukin 2, interferon gamma, interleukin 9, and interleukin 22, in peripheral blood mononuclear cell cultures. The induction of T cell activation by titanium particles suggests lymphocytes may contribute to the inflammation that mediates osteolysis in patients with metallic particulate debris after total joint replacement.