RESUMEN
Platelets regulate several polymorphonuclear leukocyte (PMN) functions. We have found that thrombin-stimulated platelets potently inhibited PMN apoptosis. Cell-free supernatant from increasing concentrations of stimulated platelets inhibited PMN apoptosis in a dose-dependent manner, with an effect similar to that of corresponding concentrations of platelets. At the plateau, platelet supernatant inhibited PMN apoptosis by 54.6 +/- 6.8%, the anti-apoptotic activity being higher than that of GM-CSF and comparable to that of LPS. Neither IL-1ra nor a combination of anti-IL1alpha + betamAb affected the activity of platelet supernatant. In contrast a mAb recognizing the active form of TGF-beta1 significantly decreased this activity. Moreover, exogenous TGF-beta1 inhibited PMN apoptosis in a dose-dependent manner. The active form of this cytokine was indeed present in the supernatant of stimulated platelets at a concentration able to elicit an anti-apoptotic effect. The p38 MAPK inhibitor SB203580 prevented the anti-apoptotic effect of TGF-beta1 in a dose-dependent manner. Interestingly, it also prevented the anti-apoptotic effect of IL-1alpha, but not that of GM-CSF, LPS and dexamethasone. In conclusion, we report for the first time that PMN apoptosis is potently inhibited by platelet-released mediators, that TGF-beta1 mediates an important part of this effect, and that p38 MAPK is involved in the TGF-beta1 signaling leading to its anti-apoptotic effect. These results provide novel evidence to support the central role of platelets in inflammation.
Asunto(s)
Apoptosis/efectos de los fármacos , Neutrófilos/citología , Factor de Crecimiento Transformador beta/fisiología , Plaquetas/metabolismo , Técnicas de Cultivo de Célula , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Imidazoles/farmacología , Lipopolisacáridos/farmacología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/fisiología , Piridinas/farmacología , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
We have evaluated the effects of dexamethasone (Dex) alone or in combination with interleukin (IL)-10 or transforming growth factor-beta 1 (TGF-beta 1) on human T cell proliferation. Both IL-10 and TGF-beta 1 significantly decreased the Dex concentration needed to inhibit T cell proliferation by 50% (IC50). Dex in combination with IL-10 completely inhibited T cell proliferation, even when IL-10 alone was ineffective, as in the case of phytohemagglutinin-induced T cell proliferation. The evaluation of the results according to the isobole method displayed a potent synergistic activity between Dex and IL-10, whereas the combination of Dex with TGF-beta 1 was additive. IL-10, but not TGF-beta 1, enhanced the inhibitory effect of Dex on IL-2 production. IL-2 and IL-4 only partly antagonized the antiproliferative effect of the combinations. IL-4 was as effective as IL-2 in antagonizing the combination of Dex with TGF-beta 1, but significantly less effective against the combination of Dex with IL-10. IL-10 and TGF-beta 1 are thus able to potentiate the Dex inhibitory effect on T cell proliferation and could be regarded as potential agents for future immunosuppressive protocols.
Asunto(s)
Dexametasona/farmacología , Inmunosupresores/farmacología , Interleucina-10/farmacología , Activación de Linfocitos/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Interleucina-2/biosíntesis , Interleucina-2/genética , Interleucina-2/farmacología , Interleucina-4/farmacología , ARN Mensajero/análisis , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
A role in tumor progression has been proposed for transforming growth factor-beta 1 (TGF beta 1) and interleukin (IL)-8 as well as for IL-1, which itself induces the production of TGF beta 1 and IL-8 in many cell types. TGF beta 1 and IL-8 production and their regulation by IL-1 in five non-small-cell (NSC) lung tumor cell lines were evaluated. Moreover, their levels were evaluated in 29 NSC lung tumors. All cell lines constitutively produced TGF beta 1, and three produced IL-8. After IL-1 beta treatment, TGF beta 1 production was upregulated in two cell lines, whereas IL-8 production was markedly upregulated in two, induced in one, and unmodified in two. In tumors, the levels of TGF beta 1, IL-8, and IL-1 beta were higher than in normal counterparts (p < 0.001), and a positive correlation between IL-8 and IL-1 beta levels (p < 0.001) was found. TGF beta 1, IL-8, and IL-1 beta mRNA expression was examined in 12 tumors. TGF beta 1 mRNA was detected in all cases, IL-8 mRNA in 7, and IL-1 beta MRNA was undetectable. TGF beta 1, IL-8, and IL-1 beta immunoreactivity was then studied by immunohistochemistry. TGF beta 1 and IL-8 immunoreactivity was observed in neoplastic cells; IL-1 beta immunoreactivity was observed in mononuclear cells. In conclusion, in tumors IL-1 beta levels positively correlated with those of IL-8, and IL-1 beta as well as TGF beta 1 and IL-8 levels were significantly higher than in normal tissues.