PubMed · 7805699
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E C Huskisson. 1993. Prizes!. https://pubmed.ncbi.nlm.nih.gov/7805699/
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The nuclear factor kappaB (NF-kappaB) is thought to be crucially involved in the gene activation of several cytokines, including tumor necrosis factor alpha (TNF). Previously, we showed that fibroblast conditioned medium (FCM) is able to inhibit both TNF mRNA accumulation and protein release in peripheral blood-derived human monocytes (PBM) stimulated with lipopolysaccharide (LPS). In this study we have investigated the effect of FCM on the LPS-induced DNA-binding activity of NF-kappaB, by means of electrophoretic shift assay (EMSA). We provide evidence that FCM strongly inhibits the LPS-induced NF-kappaB activation in PBM. Furthermore, we show that exogenous PGE2 mimics the NF-kappaB inhibitory effect of FCM. On the other hand, FCM produced in the presence of indomethacin does not inhibit NF-kappaB activation by LPS. Our results lend further support to the hypothesis that inflammatory and immune responses of monocytes/macrophages may be modulated at the molecular level by signals originating from tissue structural cells such as fibroblasts.
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 other activation stimuli. METHODS: The expression of CD11b and L-selectin during neutrophil activation with tumor necrosis factor alpha (TNF alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), FMLP, phorbol myristate acetate (PMA), and calcium ionophore A23187 was assessed by flow cytometry. Enzyme-linked immunosorbent assays were used to quantitate soluble L-selectin shed after neutrophil stimulation. Enzyme release was measured to determine neutrophil degranulation by proinflammatory stimuli. Changes in affinity state of beta 1 and beta 2 integrins after neutrophil and T lymphocyte stimulation were assessed, by 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 expression induced by TNF alpha, GM-CSF, and FMLP, but not those induced by PMA or A23187. Furthermore, piroxicam significantly decreased the amount of L-selectin shed by cytokine-treated neutrophils, whereas it did not exert this effect on PMA- or A23187-treated neutrophils. Piroxicam also decreased the release of gelatinase and lysozyme induced by TNF alpha, but not by PMA. Interestingly, piroxicam prevented the conformational changes that beta 2 integrins underwent upon activation of neutrophils: the appearance of the activation epitope of CD11b, detected by the CBRM1/5 MAb, was blocked by piroxicam in TNF alpha-treated neutrophils. Moreover, in chemokine-treated T lymphocytes, the expression of activation epitopes on beta 1 integrins was also diminished by piroxicam. In contrast, this NSAID did not affect the beta 1 integrin conformational changes induced by PMA or Mn++. CONCLUSION: Our results indicate that members of the oxicam family are able to interfere with events of neutrophil function, such as their degranulation and cytokine-mediated activation changes in adhesion molecules, both in neutrophils and in lymphocytes. Such effects may significantly contribute to the antiinflammatory activity of these drugs.