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Modulation of the Production of Cytokines in Titanium-Stimulated Human Peripheral Blood Monocytes by Pharmacological Agents. The Role of cAMP-Mediated Signaling Mechanisms*

THEODORE A. BLAINE, M.D., PAUL F. POLLICE, M.D., RANDY N. ROSIER, M.D., PH.D., PAUL R. REYNOLDS, PH.D., J. EDWARD PUZAS, PH.D. and REGIS J. O'KEEFE, M.D., ROCHESTER, NEW YORK

Investigation performed at the Department of Orthopaedics, University of Rochester School of Medicine and Dentistry, Rochester

Cytokines secreted by activated macrophages play a role in the development of osteolysis adjacent to prosthetic joints. To determine whether the synthesis of cytokines can be inhibited by pharmacological agents, we studied the role of the cAMP-protein kinase A signal transduction pathway in the synthesis of interleukin-6 and tumor necrosis factor- and examined the effect of potential pharmacological regulators of this pathway in human peripheral blood monocytes stimulated with titanium particles. Dibutyryl cAMP enhanced the synthesis of interleukin-6 by titanium-stimulated monocytes and resulted in a marked increase (maximum, seventyfold) in the synthesis of interleukin-6 even in the absence of titanium particles. However, the active analogs (agonists) of cAMP, dibutyryl cAMP and Sp cAMP, inhibited the production of tumor necrosis factor- by titanium-stimulated monocytes (the maximum effects resulted in complete inhibition), while the cAMP antagonist, Rp cAMP, enhanced the production of tumor necrosis factor-. Additional agents that alter the intracellular levels of cAMP were examined for their effects on the synthesis of cytokines. Prostaglandins E₁ and E₂ were potent inhibitors of the synthesis of tumor necrosis factor- but stimulated the synthesis of interleukin-6. In contrast, indomethacin enhanced the stimulatory effects of titanium particles on tumor necrosis factor-, resulting in a more than threefold increase in the maximum levels of tumor necrosis factor-. Phosphodiesterase inhibitors, such as isobutyryl methylxanthine and pentoxifylline, which increase intracellular levels of cAMP, caused a decrease in the production of tumor necrosis factor- and an increase in the production of interleukin-6. In contrast, the fluoroquinolone antibiotic ciprofloxacin, which is also a phosphodiesterase inhibitor, caused a dose-dependent inhibition of the synthesis of both tumor necrosis factor- and interleukin-6 by titanium-stimulated monocytes, suggesting that ciprofloxacin suppresses the synthesis of interleukin-6 through a mechanism that is independent of cAMP. CLINICAL RELEVANCE: Pharmacological agents, in combination with efforts at reducing the generation of wear debris, may lead to novel therapeutic strategies to prevent the loosening of implants. Alteration of the synthesis of cytokines in response to pharmacological manipulation of the cAMP-protein kinase A signaling pathway suggests that these events are regulated by normal physiological mechanisms in titanium-stimulated human peripheral blood monocytes rather than by an irreversible toxic response. The differential response of tumor necrosis factor- and interleukin-6 to agents that alter intracellular levels of cAMP indicates that these two cytokines are independently regulated. Thus, pharmacological strategies to inhibit the release of cytokines may need to involve multiple agents to inhibit diverse regulatory pathways. Basic-science studies identifying the pathways involved in titanium-mediated synthesis of cytokines are essential for the efficient design and selection of inhibitory agents.

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