Cytokines and inflammation - GDR CNRS 3048  


  HEADProf CAVAILLON Jean-Marc / jmcavail@pasteur.fr
  MEMBERSDr ADIB-CONQUY Minou / Dr CIORNEI Cristina / FITTING Catherine / Dr. IBRAHIM-GRANET Oumaïma / KAPETANOVIC Ronan / Dr KIM Oh Yoen / Dr PHILIPPART François


  Annual Report

Cytokine induction by bacteria and pathogen-associated molecular patterns (PAMPs).

In the past, we have performed numerous studies in collaboration with Dr. Martine Caroff (IBBM, Orsay) to study the relationship between the structures of lipopolysaccharides (LPS) from Gram-negative bacteria and their capacity to induce cytokine production. We now investigate the capacity of whole bacteria to induce cytokine. We have studied the influence of the bacterial status (i.e. planctonic versusbiofilm) on the capacity of live bacteria to activate phagocytes, and we compared the LPS structure of Pseudomonas aeruginosa derived from planctonic and biofilm cultures. In addition, we investigated the contribution of phagocytosis by monocytes and macrophages in the initiation of cytokine production in response to heat-killed Staphylococcus aureus, and the relative contribution of the Toll-Like Receptor (TLR) 2 and the intracellular sensor Nod2. We also studied the interaction ofAspergillus fumigatuswith alveolar macrophages by investigating the signaling and the inflammatory response involved in the innate immunity against this opportunistic fungus. Anin vivoimaging model ofA. fumigatusinfection in mouse has been developed to follow the infectious process.

Endotoxin- and TLR-tolerance

The TLR-tolerance phenomenon is a complex orchestrated counter regulatory response to inflammation. We studied the cross-talk between different TLR agonists to induce tolerance. In contrast to other mouse mononuclear phagocytes, alveolar macrophages do not display endotoxin tolerance, and we currently study the relative contribution of GM-CSF and gamma-interferon to prevent endotoxin tolerance in the alveolar environment.

Paradoxical effects of IL-10

IL-10 is a well known anti-inflammatory cytokine that prevents the production of pro-inflammatory cytokine. Inin vitro experiments, we previously showed that the adherence of monocytes is a key parameter that allows the observation of the well-characterized property of IL-10. Surprisingly, in the absence of adherence, IL-10 can enhance LPS-induced TNF production and turn-off genes that are otherwise turned-on (e.g. SOCS 2 & 3), and vice versa. We have now developed a mouse model that allows us to study this paradoxical property of IL-10.

Biomedical research

We study the alteration of the immune status of patients with sepsis and systemic inflammatory response syndrome (SIRS; e.g. resuscitated patients after cardiac arrest; major trauma; vascular surgery) (for a review see: Cavaillon & Adib-Conquy M. Contr. Nephrol. 2007, 156: 101. Many inflammatory markers are found in plasma of sepsis and SIRS patients (Adib-Conquy & Cavaillon J-M. FEBS Lett. 2007, 581: 3723). Some of them are claimed to be specific markers of infection (e.g. procalcitonin, soluble TREM-1). However, that their plasma levels could also be very high in the absence of infection, such as in patients who died after after cardiac arrest and resuscitation (Adib-Conquy et al. Shock 2007, 28: 406).

In collaboration with Dr. Rudi Beyaert (Ghent University) we studied the involvement of ABIN-3, an intracellular negative regulator of the TLR4-dependent pathway and NF-κB activation (Wullaert et al. J Biol Chem. 2007; 282: 81), in the hyporeactivity of septic patients monocytes. We also analyzed the effect of corticosteroid treatment of these patients on ABIN-3 expression (Verstrepen et al.J Cell Mol Med, in press).Recently, the inflammatory status, apoptosis and endotoxinemia were investigated in brain dead patients (in collaboration with Dr Christophe Adrie, Delafontaine hospital, Saint-Denis).

The reduced expression of HLA-DR onto CD14+ monocytes is a marker of the altered immune status. It is currently under study in patients who undergo abdominal aortic surgery (in collaboration with Prof. P. Coriat, Hôpital Pitié-Salpétrière). In addition, we study in these patients the translocation of LPS and peptidoglycan from the gut.

Finally, we have studied blood and sputum neutrophils of cystic fibrosis patients. We have shown by macroarray technology that numerous genes are turned-on even before bacterial colonization of the lungs, and that airway neutrophils are insensitive to IL-10 inhibitory signaling (Petit-Bertron et al. Cytokine 2008, 41, 54; Adib-Conquy et al. Mol Med. 2008, 14, 36).

Keywords: Innate immunity, Pathogen associated molecular patterns, endotoxin, cytokines, sepsis, acute inflamation

Cytoinf.jpg

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 (Annane D, Bellissant E, Cavaillon J-M (2005) Septic Shock. The Lancet 365: 63-78).



  Publications

Fitting C, Dhawan S, Cavaillon J-M (2004) Compartmentalization of endotoxin tolerance. J. Infect. Dis. 189: 1295-1303

Maxime V, Fitting C, Annane D, Cavaillon J-M (2005) Corticoids normalize leukocyte production of macrophage migration inhibitory factor in septic shock. J. Infect. Dis. 191: 138-144

Fritz H.J., Girardin S.E., Fitting C., Werts C., Mengin-Lecreulx D., Caroff M., Cavaillon J-M., Philpott D.J., Adib-Conquy M. (2005) Synergistic stimulation of monocytes and dendritic cells by Toll-like receptor 4, Nod1- and Nod2-activating agonists. Eur. J. Immunol. 2005, 35, 2459-2470

Adib-Conquy M, Adrie C, Fitting C, Gattolliat O, Beyaert R, Cavaillon J-M (2006) Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit Care Med. 34: 2377-2385

Kapetanovic R., Nahori M-A., Balloy V, Fitting C., Philpott D.J., Cavaillon J-M., Adib-Conquy M (2007) Contribution of phagocytosis and intracellular sensing for cytokine production by Staphylococcus aureus-activated macrophages. Infect. Immun. 75: 830-837



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Activity Reports 2007 - Institut Pasteur
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