PREVENTION OF CYTOKINE-INDUCED CHANGES IN LEUKOCYTE ADHESION RECEPTORS BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS FROM THE OXICAM FAMILY

Objective. To explore the effect of the nonsteroidal antiinflammatory drugs (NSAIDs) piroxicam and meloxicam on quantitative and qualitative changes in leukocyte adhesion receptors induced by cytokines and othe r activation stimuli. Methods. The expression of CD11b and L-selectin during neutrophil activation with tumor necrosis factor alpha (TNF alp ha), granulocyte-macrophage colony-stimulating factor (GM-CSF), FMLP, phorbol myristate acetate (PMA), and calcium ionophore A23187 was asse ssed by flow cytometry. Enzyme-linked immunosorbent assays were used t o quantitate soluble L-selectin shed after neutrophil stimulation. Enz yme release was measured to determine neutrophil degranulation by proi nflammatory stimuli. Changes in affinity state of beta 1 and beta 2 in tegrins after neutrophil and T lymphocyte stimulation were assessed, b y flow cytometry, using the monoclonal antibodies (MAb) HUTS-21 (anti- beta 1) and CBRM1/5 (anti-CD11b), which recognize activation-dependent epitopes on these two integrins. Results. Pretreatment of neutrophils with either NSAID prevented the changes in L-selectin and CD11b expre ssion induced by TNF alpha, GM-CSF, and FMLP, but not those induced by PMA or A23187. Furthermore, piroxicam significantly decreased the amo unt of L-selectin shed by cytokine-treated neutrophils, whereas it did not exert this effect on PMA- or A23187-treated neutrophils. Piroxica m also decreased the release of gelatinase and lysozyme induced by TNF alpha, but not by PMA. Interestingly, piroxicam prevented the conform ational changes that beta 2 integrins underwent upon activation of neu trophils: the appearance of the activation epitope of CD11b, detected by the CBRM1/5 MAb, was blocked by piroxicam in TNF alpha-treated neut rophils. Moreover, in chemokine-treated T lymphocytes, the expression of activation epitopes on beta 1 integrins was also diminished by piro xicam. In contrast, this NSAID did not affect the beta 1 integrin conf ormational changes induced by PMA or Mn++. Conclusion. Our results ind icate that members of the oxicam family are able to interfere with eve nts of neutrophil function, such as their degranulation and cytokine-m ediated activation changes in adhesion molecules, both in neutrophils and in lymphocytes. Such effects may significantly contribute to the a ntiinflammatory activity of these drugs.