Co-signals influencing LPS-induced cytokines production

[Adapted from Cavaillon & Duff. IN The cytokine Network and Immune Function, Thèze Ed. 1999]

Concomitant signals act synergistically. During an infectious process host’s leukocytes (e.g. macrophages) are responding to exogenous danger signals that are the pathogens associated molecular patterns (PAMPs). The response is amplified by endogenous mediators released during the anti-infectious response and by co-factors or concomitant stressful events, including endogenous danger signals (alarmins) or iatrogenic events.

[Adib-Conquy & Cavaillon. Febs Let, 2007, 581, 3723]

Activating and inhibiting signals modulate monocytes and macrophages functions. Monocytes produce a large panel of peptides, proteins, glycoproteins, lipid mediators, and free radicals that contribute to their bioactivity. The electron microscopy picture depictes the round and veiled circulating monocyte and its differentiation into adhering macrophage.

Abbreviation : GM-CSF: granulocyte-macrophage coony stimulating factor; IFN: interferon; IL-: interleukin;
LPS: lipoplysaccharide; LTA: lipoteichoic acid; PGN: peptidoglycan; TGF: transforming growth factor.

[Cavaillon & Adib-Conquy. Crit. Care Med., 2005, 33, S506]

Pro- versus anti-inflammatory cytokines : myth or reality (Cell. Mol. Biol. 2001, 47, 695)
[Adapted from Magritte]

Within 10 years, the main pro- and anti-inflammatory cytokines were identified in sera of sepsis patients.

[Adapted from Cavaillon et al. Scand. J. Infect. Dis.2003, 33, 535]

SIRS versus CARS : Very soon after an insult, both pro- and anti-inflammatory responses are initiated concomitantly, rather than in a two-wave process.

[Cavaillon et al. J. Endotoxin Res. 2001, 7, 85]


Circulating cytokines: the tip of the iceberg. Detection of cytokines in biological fluids can be achieved only after all environmental receptors have captured available cytokines. Accordingly, it is only the excess of production that can allow such a detection.

[Cavaillon et al. Circ. Shock 1992, 38, 145]


Cell-associated cytokines : analysis of cell-associated cytokines appears as a very sensitive measurement that can allow the detection of the cytokine at its source or can detect cytokine among environmental cells.

[Cavaillon J-M. Prog. Inflam. Res.,1999, 95-119]


From bacteria to disease. During infection, host cells sense bacterial derived products (lipopolysaccharide, LPS; peptidoglycan, PGN; DNA…] via specific receptors (Toll-like receptors, TLR; peptidoglycan recognition proteins, PGRP; nucleotide-binding oligomerization domain, Nod). The activation of leukocyte results in the production of numerous mediators of innate immunity and inflammation (tumor necrosis factor, TNF; interleukin-1, IL-1; nitric oxide, NO…). Other events triggered by bacterial derived products (complement activation, coagulation) amplify the inflammatory process. An exacerbated production of inflammatory mediators contribute to organ dysfunction and eventually death. Concomitantly, the inflammation process is counter-regulated by the induction of anti-inflammatory mediators (interleukin-10, IL-10; IL-1 receptor antagonist, IL-1ra; soluble TNF receptors, sTNFR…), acute phase proteins (including LPS binding protein, LBP; soluble CD14, sCD14…), neuropeptides and hormones. These mediators together with the occurrence of apoptosis of leukocytes contribute to an altered immune status

[Annane D., Bellissant E., Cavaillon J-M. Septic Shock, The Lancet, 2005, 365, 63].


Influence of inflammation on immune status : Numerous events contribute to systemic inflammation that is associated with an alteration of the immune status, as assessed by various modifications and reduced immune responsiveness.
[Cavaillon et al. Contrib. Nephrol. 2004, 144, 76-93]


LPS-induced intracellular signaling cascade. Following its binding to CD14, LPS interacts with MD2 / TLR4 signaling complex. Two main pathways are activated either MyD88-dependent leading to NF-kappaB activation and IL-1 and TNF production or TRAM/TICAM-2 and TRIF/TICAM-1 dependent leading to the activation IRF3 and interferon-? (IFNgamma) production. Other down-stream pathways lead to the activation of Sp1, a prerequisite for IL-10 production, while pI-3 kinase is involved in IL-1ra induction. Numerous intracellular molecules (MyD88s, Tollip, IRAK-M, SOCS-1, pI-3-kinase) and cell surface molecules (ST2, SIGIRR) down-regulate the activating cascade. During sepsis, reprogrammation of leukocyte is associated with some altered (grey background), or enhanced (yellow background) cellular signaling pathways that lead to the modified production of TNF, IL-1beta IL-1ra and IL-10 in response to TLR4 ligands. This cartoon illustrates our published works (Adib-Conquy et al J. Leuk. Biol. 2001, 70:30; Adib-Conquy et al. Am. J. Respir. Crit Care Med. 2003, 168; 158; Adib-Conquy et al. Crit. Care Med. 2006, 34: 2377), and other reports (Learn et al. J. Biol. Chem. 2001; 276:20234; Solomon et al. J. Clin. Invest. 1998; 102: 2019).

[Adapted from Annane D, Bellissant E, Cavaillon JM. Septic Shock, The Lancet, 2005, 365: 63]


Negative regulators of the TLR4-dependent signaling. During the last few years a great number of numerous intracellular molecules that counteract the TLR4-MyD88-dependent signaling pathway, have been identified. Their involvement in endotoxin tolerance and in leukocyte reprogramming of circulating cells derived from septic and critically ill patients is under investigation

[Adapted from Cavaillon & Adib-Conquy, Crit. Care 2006, 10, 233]


The vicious cycle of perpetuation of inflammation and its spread from one compartment to another. During systemic inflammatory response syndrome (e.g. hemorrhagic shock, sepsis…) large amounts of inflammatory mediators are found within the blood stream. They can act on different organs and induce tissue injury that in turn will favor the production of inflammatory mediators, or in the case of the gut, the systemic delivery of endotoxin and other microbial agents. The cross-talk between tissues is also mediated by local delivery of neuromediators that can amplify or limit the inflammatory process. Glucocorticoids, acute phase proteins, and locally produced anti-inflammatory cytokines and mediators (e.g. IL-10, TGFbeta, soluble TNFR, IL-1Ra - not shown on the figure), contribute to dampen the inflammatory process.

[Cavaillon & Annane, J. Endotoxin Res. 2005, 12, 151]


Parameters that affect outcome after infection. The natural evolution of a systemic inflammatory disorder or a sepsis is greatly influenced by parameters linked to the pathogen(s), the ICU treatments and by many others elements associated with the patient.

[Cavaillon & Adrie – IN Sepsis and Non-infectious Systemic Inflammation:
From Biology to Critical Care, Wiley Sept. 2008]


Nod-like receptors and their ligands

[adapted from Kapetanovic & Cavaillon. Expert Opin Biol. Ther. 2007, 7, 907]

Damage associated molecular patterns (DAMPs) or alarmins

The concept of endogenous danger signal proposed in 1994 by Polly Matzinger was confirmed through the years. Nowadays, numerous endogenous molecules released by damaged tissues and necrotic cells activate innate immune response through different pattern recognition receptors (PRRs)

[adapted from Bull. Assoc. Anciens Elèves Inst. Pasteur 2007, 49: 58] 


The different steps of the response against microbial pathogens. During the infectious process, pathogens are detected by the humoral components (i.e. complement system and natural antibodies). In addition, leukocytes recognize pathogen- associated molecular patterns (PAMPs), initiating the immune response. Phagocytosis is increased, anti-microbial peptides are produced and cytokines are secreted. These latter molecules cause a systemic response, acting on leukocytes, endothelium, bone marrow, central nervous system and liver.

[Kapetanovic & Cavaillon. Expert Opin Biol. Ther. 2007, 7, 907]

Mechanism of interleukin-1beta release through the activation of inflammasome

Interleukin-1beta (IL-1beta), previously known as endogenous pyrogen, osteoclast activating factor, catabolin, hemopoietin-1, lymphocyte activating factor, or epidermal-derived thymocyte activating factor is produced as an inactive precursor form upon cell activation. Its release requires the activation of different molecules gather under the name of "inflammasome" by Jürg Tschopp. The activation of inflammasome leads to the active form of caspase-1, the enzyme required for the maturation of IL-1beta. The release of IL-1beta requires the activation of the cell by ATP through its P2X7 receptor, the involvement of K+ and Ca+ chanels and the action of a phosphatidylcholine-sepcific phospholipase.

[adapted from Bull. Assoc. Anciens Elèves Inst. Pasteur 2007, 49: 58]

Cytokines as coordinators of regulated processes taking place in bacteria-loaded sites

If bacteria get access to tissues, resident cells release inflammatory cytokines that boost anti-infectious process, and chemokines that attract leukocytes from the blood compartment to further fight against the infection.

[adapted from J-M. Cavaillon, "Molecular mediators: cytokines" in Encyclopedia of Molecular Cell Biology and Molecular Medicine. Vol. 8, pp.431-460 Ed. Robert A. Meyers]

Altered immune status during sepsis and systemic inflammatory response syndrome (SIRS)

[Cavaillon and Adrie – In "Sepsis and Non-Infectious Systemic Inflammation – From Biology to Critical Care". Wiley-Blackwell Publ. 2009]

Activation of NK cells by bacterial PAMPs. NK cells are activated within a network of accessory cells that sense bacterial pathogen associated molecular patterns (PAMPs). The activation of accessory cells leads to the production of cytokines that contribute to the functional activation of NK cells, while sensing of PAMPs by NK cells themselves further enhances their reactivity. All listed cytokines have been shown to amplify NK cells activity, either alone or in synergy. Negative signals can be directly delivered to NK cells (e.g. IL-10 and TGF¾ produced by regulatory T cells (Tregs), prostaglandins, glucocorticoids) or indirectly by down-regulating the function of accessory cells.
(From Souza-Fonseca-Guimaraes et al. Mol Med. 2012 Mar 30;18(1):270-85)


Microbial products (PAMPs) released during infection, and endogenous danger molecules (DAMPs) released by necrotic cells and after tissue insult initiate the innate immune response on the site of infection following their recognitions by specific receptors (PPRs).
[Adapted from Cavaillon J-M. IN Infectiologie en réanimation , P. Charbonneau & M. Wolff, Eds, Springer 2013]