RESUMEN
IL-10 is a potent anti-inflammatory molecule, which regulates TNF-alpha at multiple levels. We investigated whether IL-10 also modulated the activity of the TNF-alpha-converting enzyme (TACE). Using an ex vivo fluorogenic assay we observed that LPS rapidly induced TACE activity in monocytes coinciding with release of soluble TNF-alpha. In the presence of IL-10, TNF-alpha production and activation of surface TACE was significantly inhibited. Paradoxically, both LPS with or without IL-10 led to accumulation of surface TACE (albeit catalytically inactive) over a 24 h period. We investigated whether this was mediated through induction of endogenous tissue inhibitor metalloproteinase-3 (TIMP-3). We found that the inhibition of TACE activity at 2 h by IL-10 was not TIMP-3 dependent but that the late accumulation of surface TACE was prevented with TIMP-3 antibodies. Furthermore, induction of endogenous TIMP-3 was observed by western blotting in both LPS- and in LPS with IL-10-treated monocytes from 6 to 8 h of culture. These results indicate that IL-10 further regulates TNF-alpha by modulating TACE activation at early time points and by contributing to the induction of TIMP-3, the natural inhibitor of active TACE, at later time points. These observations add to our understanding of inflammation and the importance of homeostatic regulators of these events.
Asunto(s)
Proteínas ADAM/metabolismo , Interleucina-10/farmacología , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Proteína ADAM17 , Anticuerpos/inmunología , Catálisis , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Células Cultivadas , Humanos , Lipopolisacáridos/farmacología , Microscopía Confocal , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Solubilidad , Inhibidor Tisular de Metaloproteinasa-3/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Regulación hacia ArribaRESUMEN
Pro- and anti-inflammatory cytokines are elevated after cardiac surgery. The control of the release of these major paracrine proteins is becoming clearer and they have been shown to be involved in the activation of the coagulation/fibrinolysis pathway, among other cascades. The association of a predominance of pro-inflammatory cytokines with morbidity in some patients, particularly following cardiac surgery, is well described but still incompletely understood. Clinical studies elucidating how clinicians may influence this cytokine release directly will improve our knowledge of the processes involved and could ultimately show benefit in better outcomes for patients.
Asunto(s)
Antifibrinolíticos/uso terapéutico , Procedimientos Quirúrgicos Cardíacos , Citocinas/metabolismo , Mediadores de Inflamación/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Ácido Tranexámico/uso terapéutico , Citocinas/efectos de los fármacos , Citocinas/fisiología , Humanos , Complicaciones Posoperatorias/metabolismoRESUMEN
Diabetes mellitus is now classified as either 'type 1' (failure of endogenous insulin production) or 'type 2' ('insulin resistance') and can be diagnosed if fasting blood glucose is >6.1 mmol/l (110mg/dl) on two separate occasions or there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. The prevalence of the disease is rising and may be as great as 12-14% in western populations aged over 40 years. Diabetes is complicated by micro- and macrovascular consequences of chronically elevated blood glucose concentrations, and diabetic patients are over-represented in hospital populations, particularly among patients requiring surgical interventions. It is associated with increased perioperative mortality and morbidity. Evidence is now accumulating that intensive glycaemic monitoring and the administration of insulin infusions to achieve tight glycaemic control are associated with an improvement of both perioperative mortality and morbidity.