INCREASED LEVELS OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 PROTEIN AND MESSENGER-RNA IN HUMAN PERIPHERAL-BLOOD MONOCYTES DUE TO TITANIUM PARTICLES

Cytokines produced by macrophages in the periprosthetic membranes surr ounding joint replacements have been implicated as causal agents in os teolysis and prosthetic loosening, The present study characterizes the response of human peripheral blood monocytes to titanium particles, M onocytes were obtained from volunteers and blood that had been donated to the American Red Cross and were cultured in the presence of titani um particles (one to three micrometers in diameter), There were consis tent dose-dependent increases in the production of TNF-alpha (tumor ne crosis factor-alpha) and IL-6 (interleukin-6) protein, with the greate st stimulation generally observed with a concentration of 6 x 10(5) to 6 x 10(6) particles of titanium per milliliter, The level of TNF-a wa s the greatest (fifty to 1000 times greater than the control level) af ter eight hours of exposure to titanium particles; the level of IL-6 w as two to five times greater than the control level after sixteen hour s of exposure, These increases were similar to those observed after st imulation,vith lipopolysaccharide and depended on de novo synthesis ra ther than on release from intracellular stores, The production of TNF- alpha was inhibited in a dose-dependent manner by the translational in hibitor cycloheximide and the transcriptional inhibitor actinomycin D, indicating the requirement for both mRNA (messenger RNA) and protein synthesis for the induction of cytokine synthesis by titanium particle s, Although the increase in the levels of cytokine mRNA in response to titanium was rapid (thirty to ninety minutes), the increase in the le vel of TNF-alpha mRNA preceded that of IL-6 mRNA, The level of TNF-alp ha mRNA was the greatest at ninety minutes and the level of IL-6 mRNA was the greatest at three hours, After stimulation with titanium parti cles, the level of TNF-alpha mRNA was increased as much as fivefold an d the level of IL-6 mRNA, as much as twelvefold, CLINICAL RELEVANCE: A wareness of the importance of wear debris particles in cytokine-induce d bone resorption has resulted in improvements in the designs of impla nts and in operative techniques to reduce wear of components, The pres ent study further elucidates the biological mechanisms involved in per iprosthetic osteolysis. Titanium-stimulated biosynthesis of the cytoki nes TNF-alpha and IL-6, which are both potent stimulators of bone reso rption, requires increases in the synthesis of both mRNA and protein b y monocytes. Are understanding of the complex mechanisms of the induct ion of cytokine synthesis by particles of wear debris will facilitate the design of pharmacological agents to control periprosthetic bone re sorption, These agents, in combination with other efforts to reduce th e generation of wear debris, may improve the longevity of orthopaedic implants.