Cytokines and inflammation


  HEADDr CAVAILLON Jean-Marc / jmcavail@pasteur.fr
  MEMBERSDr ADIB-CONQUY Minou / Dr CIORNEI Cristina / KAPETANOVIC Ronan
Dr KIM Oh Yoen / Dr PHILIPPART François


  Annual Report

In patients with sepsis or a systemic inflammatory response syndrome (SIRS) (e.g. resuscitated patients after cardiac arrest; major trauma; vascular surgery; brain death) the naturally initiated anti-inflammatory response alters their immunological status. Circulating leukocytes from SIRS patients display a reduced ex vivo capacity to produce pro-inflammatory cytokines (e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF]) in response to bacterial endotoxin (lipopolysaccharide, LPS), while the capacity to release anti-inflammatory cytokines (e.g. IL-1 receptor antagonist, IL-10) is maintained or even increased. This hyporeactivity of circulating leukocytes observed in sepsis and SIRS patients is reminiscent of the phenomenon of endotoxin tolerance (the unresponsiveness to a 2nd challenge by endotoxin after a first encounter with endotoxin), and may be associated with the increased susceptibility of these patients to nosocomial infections. We characterize the intra-cellular signaling pathways in leukocytes of sepsis and SIRS patients. We showed that the down-regulation of leukocyte reactivity is not a global defect. Our results depict the phenomenon as a "leukocyte reprogramming" rather than an "immune anergy", or an "immunosuppression" or an "immune paralysis", terms often used to characterize the immune status of critically ill patients.

The tolerance phenomenon is a complex orchestra-ted counter regulatory response to inflammation. To further characterize the molecular mechanisms that lead to the tight balance of cytokine production (figure), we study the cross-talk between extra-cellular (e.g. Toll-Like Receptors, TLR) and intracellular (e.g. Nod-like Receptors) sensors of microbial products. Microbial-derived compounds (e.g. LPS) do not fully reproduce bacterial effects. Thus, we employ whole bacteria to induce cytokine and we investigate the contribution of their phagocytosis in the initiation of cytokine production by monocytes and macrophages. We compare the influence of the bacterial status (i.e. planctonic versus biofilm) on the capacity of bacteria to activate phagocytes. We also analyze the reactivity of macrophages isolated from different compartments: the phenomenon of endotoxin tolerance is poor with alveolar macrophages but strong with peritoneal macrophages or circulating monocytes. Finally, we study the involvement of intracellular negative regulators of the TLR4-dependent pathway (e.g. ABIN-3).

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Des bactéries aux maladies infectieuses. L'interaction des molécules microbiennes avec les cellules hôtes mène à la production des cytokines, indispensables à l'immunité innée. Une production exacerbée est associée à une inflammation sévère tandis que la réponse anti-inflammatoire concomitante peut être associée à la susceptibilité accrue aux infections nosocomiales (The lancet 2005, 365, 63)

From bacteria to infectious diseases. Interaction of microbial derived molecules with host's cells leads to the production of cytokines, a prerequisite for innate immunity. Overwhelming production is associated with severe inflammation while the concomitant anti-inflammatory response may be associated with increased susceptibility to nosocomial infection (The Lancet, 2005, 365, 63)



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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