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Monocyte/macrophage activation in chronic/sterile inflammation: regulation of cytokine homeostasis

Background: The inflammatory response aims at protecting the organism by clearing out the initial cause of cell injury (e.g., microorganisms or toxins) and the consequences of such injury (e.g., necrotic cells and tissues), and in turn at initiating mechanisms designed at repairing surrounding damaged tissues. Inflammation has to be tightly controlled in time and space to avoid detrimental developments such as those seen in sepsis and chronic inflammatory diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Monocytes/macrophages play critical parts in non-septic T cell-mediated chronic inflammatory diseases as exemplified by multiple sclerosis (MS) and rheumatoid arthritis (RA). Monocytes/macrophages are the major producers of cytokines at inflammatory sites in both chronic/sterile and acute/infectious inflammation. Cell-cell contact with stimulated T lymphocytes is now considered a major pathway triggering monocytes/macrophages to produce inflammatory mediators in the absence of infectious agents. This mechanism is likely to be relevant to chronic inflammatory diseases, particularly in the perivascular region of local sites of inflammation where T lymphocytes and monocytes/macrophages are in close proximity. This is also the region where apolipoprotein A-I - a specific inhibitor of contact-mediated activation of monocytes - accumulates upon active inflammation.
Aims: The aim of our project is to characterize the molecular basis of cell-cell contact with stimulated T cells as a general strategy whereby monocytes/macrophages are triggered to produce cytokines and to differentiate/maturate. To this purpose we are currently investigating critical aspects of this mechanism by addressing the following questions: A) Which are the ligands on stimulated T lymphocytes and receptors on monocytes involved in the induction of cytokines? B) Which transduction pathways and nuclear factors in monocytes/macrophages are involved in cytokine induction by contact with stimulated T cells and not involved in acute/infectious inflammation? C) Could T cell microparticles ship contact-mediated activation of monocytes away from a distance? D) Is cellular contact with stimulated T cells involved in the differentiation of monocytes into macrophages observed at the inflammatory site? and E) Does contact-mediated activation of monocytes occurs in mouse system in a similar way as in human?
Relevance: MS and RA lead to profound disabilities on which disease-modifying treatments, have shown beneficial effects but are far to cure patients. The specific blockade of T cell contact-mediated activation of monocytes/macrophages, i.e., the blockade of pathogenic, deregulated cytokine production rather than the blockade of cytokine action constitutes a new approach to treating patients, the beneficial functions of cytokines such as that of TNF in remyelination remaining intact. Thus the identification of the extra- and intracellular factors involved in contact-mediated activation of monocyte/macrophages may lead to the characterization of new agents able to interfere with cytokine production and contribute to the identification of novel therapeutic tools and approaches.

Group's publications

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1 beta in human monocytes and multiple sclerosis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009 vol. 106(11) pp. 4355-4359
BURGER D, MOLNARFI N, WEBER MS, BRANDT K, BENKHOUCHA M, GRUAZ L, CHOFFLON M, ZAMVIL SS, LALIVE P.H.

18658195
JOURNAL OF LEUKOCYTE BIOLOGY
2008 vol. 83(4) pp. 921-927
SCANU A, MOLNARFI NICOLAS, BRANDT K, GRUAZ LYSSIA, DAYER JM, BURGER D

Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions.
MOLECULAR IMMUNOLOGY
2008 vol. 45(12) pp. 3419-3427
MOLNARFI NICOLAS, BRANDT K, GRUAZ LYSSIA, DAYER JM, BURGER D

Opposite regulation of IL-1 beta and secreted IL-1 receptor antagonist production by phosphatidylinositide-3 kinases in human monocytes activated by lipopolysaccharides or contact with T cells
JOURNAL OF IMMUNOLOGY
2007 vol. 178 pp. 446-454
MOLNARFI, N, GRUAZ, L, DAYER, JM, BURGER, D

Assays of T-cell contact dependent monocyte-macrophage functions
METHODS IN MOLECULAR MEDICINE
2007 vol. 136 pp. 139-148
BURGER D., DAYER J.M.

Anti-fibroblast antibodies detected by cell-based ELISA in systemic sclerosis enhance the collagenolytic activity and matrix metalloproteinase-1 production in dermal fibroblasts
RHEUMATOLOGY : OFFICIAL JOURNAL OF THE BRITISH SOCIETY FOR RHEUMATOLOGY
2007 vol. 46(12) pp. 1779-1785
FINESCHI S, COZZI F, BURGER D, DAYER JM, MERONI PL, CHIZZOLINI C

Is IL-I a good therapeutic target in the treatment of arthritis?
BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY
2006 vol. 20 pp. 879-896
BURGER D, DAYER JM, PALMER G, GABAY C

From cellular receptors to transduction-transcription pathways for cytokines: at which level should the inhibition be targeted in inflammation?
EXPERT OPINION ON BIOLOGICAL THERAPY
2005 vol. 5 pp. 83-96
DAYER JEAN-MICHEL, MOLNARFI NICOLAS, BURGER DANIELLE

The production of IL-1 receptor antagonist in IFN-beta-stimulated human monocytes depends on the activation of phosphatidylinositol 3-kinase but not of STAT1
JOURNAL OF IMMUNOLOGY
2005 vol. 174 pp. 2974-2980
MOLNARFI NICOLAS, HYKA NEVILA, GRUAZ LYSSIA, DAYER JEAN-MICHEL, BURGER DANIELLE

T cell contact-mediated activation of respiratory burst in human polymorphonuclear leukocytes is inhibited by high-density lipoproteins and involves CD18
JOURNAL OF LEUKOCYTE BIOLOGY.
2005 vol. 77 pp. 52-58
CETTOUR ROSE PHILIPPE, NGUYEN TXK, SERRANDER LENA, KAUFMANN MARIE-THÉRÈSE, DAYER JEAN-MICHEL, BURGER DANIELLE, ROUX-LOMBARD-LATUNE PASCALE

Apolipoprotein A-I infiltration in rheumatoid arthritis synovial tissue: a control mechanism of cytokine production?
ARTHRITIS RESEARCH & THERAPY
2004 vol. 6 pp. 563-566
BRESNIHAN B, GOGARTY M, FITZGERALD O, DAYER JM, BURGER D

The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes
ARTHRITIS RESEARCH & THERAPY
2004 vol. 6 pp. 181-189
PALMER G, BURGER D, MEZIN F, MAGNE D, GABAY C, DAYER JM, GUERNE PA

Cell-cell interactions and tissue damage in rheumatoid arthritis
AUTOIMMUNITY REVIEWS
2004 vol. 3 suppl. 1 pp. 7-73
DAYER JM, BURGER D

Adrenal insufficiency: the link between low apolipoprotein A-I levels and poor outcome in the critically ill?
CRITICAL CARE MEDICINE
2004 vol. 32 pp. 1978-1979
CHENAUD CATHERINE, MERLANI PAOLO, ROUX-LOMBARD-LATUNE PASCALE, BURGER DANIELLE, HARBARTH STEPHAN, LUYASU SAMUEL, GRAF JEAN-DANIEL, DAYER JEAN-MICHEL, RICOU BARA

Low apolipoprotein A-I level at intensive care unit admission and systemic inflammatory response syndrome exacerbation
CRITICAL CARE MEDICINE
2004 vol. 32 pp. 632-637
CHENAUD C, MERLANI P, ROUX LOMBARD P, BURGER D, HARBARTH S, LUYASU S, GRAF JD, DAYER JM, RICOU B

Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease.
JOURNAL OF AUTOIMMUNITY
2004 vol. 23 pp. 353-360
VUILLEUMIER NICOLAS, REBER GUIDO, JAMES RICHARD, BURGER DANIELLE, DE MOERLOOSE PHILIPPE, DAYER JEAN-MICHEL, ROUX-LOMBARD-LATUNE PASCALE

Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the production of IL-1 receptor antagonist by human adipose tissue
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
2004 vol. 89 pp. 2652-2658
JUGE-AUBRY CE, SOMM E, CHICHEPORTICHE R, BURGER D, PERNIN A, PITTET-CUENOD B, QUINODOZ P, GIUSTI V, DAYER JM, MEIER CA

Differential induction of IL-1 beta and TNF by CD40 ligand or cellular contact with stimulated T cells depends on the maturation stage of human monocytes
JOURNAL OF IMMUNOLOGY
2004 vol. 173 pp. 1292-1297
BURGER D, MOLNARFI N, GRUAZ L, DAYER JM

Opposite effects of IFN-beta on cytokine homeostasis in LPS- and T cell contact-activated human monocytes
JOURNAL OF NEUROIMMUNOLOGY.
2004 vol. 146 pp. 76-83
MOLNARFI N, GRUAZ L, DAYER JM, BURGER D

Research's domains




DATABASE-RESEARCH	GROUP OF CLINICAL PATIENT RESEARCH

Danielle BURGER	Head of group CV	Research subject	Members of the group


	Links about the group Danielle BURGER HUG/Serv. immuno et allergo. Hans Wilsdorf Laboratory Rue Gabrielle-Perret-Gentil 4 1211 Genève 14 Suisse Danielle.Burger@hcuge.ch Tel.: 022 37 29 376 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Monocyte/macrophage activation in chronic/sterile inflammation: regulation of cytokine homeostasis Background: The inflammatory response aims at protecting the organism by clearing out the initial cause of cell injury (e.g., microorganisms or toxins) and the consequences of such injury (e.g., necrotic cells and tissues), and in turn at initiating mechanisms designed at repairing surrounding damaged tissues. Inflammation has to be tightly controlled in time and space to avoid detrimental developments such as those seen in sepsis and chronic inflammatory diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Monocytes/macrophages play critical parts in non-septic T cell-mediated chronic inflammatory diseases as exemplified by multiple sclerosis (MS) and rheumatoid arthritis (RA). Monocytes/macrophages are the major producers of cytokines at inflammatory sites in both chronic/sterile and acute/infectious inflammation. Cell-cell contact with stimulated T lymphocytes is now considered a major pathway triggering monocytes/macrophages to produce inflammatory mediators in the absence of infectious agents. This mechanism is likely to be relevant to chronic inflammatory diseases, particularly in the perivascular region of local sites of inflammation where T lymphocytes and monocytes/macrophages are in close proximity. This is also the region where apolipoprotein A-I - a specific inhibitor of contact-mediated activation of monocytes - accumulates upon active inflammation. Aims: The aim of our project is to characterize the molecular basis of cell-cell contact with stimulated T cells as a general strategy whereby monocytes/macrophages are triggered to produce cytokines and to differentiate/maturate. To this purpose we are currently investigating critical aspects of this mechanism by addressing the following questions: A) Which are the ligands on stimulated T lymphocytes and receptors on monocytes involved in the induction of cytokines? B) Which transduction pathways and nuclear factors in monocytes/macrophages are involved in cytokine induction by contact with stimulated T cells and not involved in acute/infectious inflammation? C) Could T cell microparticles ship contact-mediated activation of monocytes away from a distance? D) Is cellular contact with stimulated T cells involved in the differentiation of monocytes into macrophages observed at the inflammatory site? and E) Does contact-mediated activation of monocytes occurs in mouse system in a similar way as in human? Relevance: MS and RA lead to profound disabilities on which disease-modifying treatments, have shown beneficial effects but are far to cure patients. The specific blockade of T cell contact-mediated activation of monocytes/macrophages, i.e., the blockade of pathogenic, deregulated cytokine production rather than the blockade of cytokine action constitutes a new approach to treating patients, the beneficial functions of cytokines such as that of TNF in remyelination remaining intact. Thus the identification of the extra- and intracellular factors involved in contact-mediated activation of monocyte/macrophages may lead to the characterization of new agents able to interfere with cytokine production and contribute to the identification of novel therapeutic tools and approaches. Group's publications Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1 beta in human monocytes and multiple sclerosis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2009 vol. 106(11) pp. 4355-4359 BURGER D, MOLNARFI N, WEBER MS, BRANDT K, BENKHOUCHA M, GRUAZ L, CHOFFLON M, ZAMVIL SS, LALIVE P.H. 18658195 JOURNAL OF LEUKOCYTE BIOLOGY 2008 vol. 83(4) pp. 921-927 SCANU A, MOLNARFI NICOLAS, BRANDT K, GRUAZ LYSSIA, DAYER JM, BURGER D Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions. MOLECULAR IMMUNOLOGY 2008 vol. 45(12) pp. 3419-3427 MOLNARFI NICOLAS, BRANDT K, GRUAZ LYSSIA, DAYER JM, BURGER D Opposite regulation of IL-1 beta and secreted IL-1 receptor antagonist production by phosphatidylinositide-3 kinases in human monocytes activated by lipopolysaccharides or contact with T cells JOURNAL OF IMMUNOLOGY 2007 vol. 178 pp. 446-454 MOLNARFI, N, GRUAZ, L, DAYER, JM, BURGER, D Assays of T-cell contact dependent monocyte-macrophage functions METHODS IN MOLECULAR MEDICINE 2007 vol. 136 pp. 139-148 BURGER D., DAYER J.M. Anti-fibroblast antibodies detected by cell-based ELISA in systemic sclerosis enhance the collagenolytic activity and matrix metalloproteinase-1 production in dermal fibroblasts RHEUMATOLOGY : OFFICIAL JOURNAL OF THE BRITISH SOCIETY FOR RHEUMATOLOGY 2007 vol. 46(12) pp. 1779-1785 FINESCHI S, COZZI F, BURGER D, DAYER JM, MERONI PL, CHIZZOLINI C Is IL-I a good therapeutic target in the treatment of arthritis? BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY 2006 vol. 20 pp. 879-896 BURGER D, DAYER JM, PALMER G, GABAY C From cellular receptors to transduction-transcription pathways for cytokines: at which level should the inhibition be targeted in inflammation? EXPERT OPINION ON BIOLOGICAL THERAPY 2005 vol. 5 pp. 83-96 DAYER JEAN-MICHEL, MOLNARFI NICOLAS, BURGER DANIELLE The production of IL-1 receptor antagonist in IFN-beta-stimulated human monocytes depends on the activation of phosphatidylinositol 3-kinase but not of STAT1 JOURNAL OF IMMUNOLOGY 2005 vol. 174 pp. 2974-2980 MOLNARFI NICOLAS, HYKA NEVILA, GRUAZ LYSSIA, DAYER JEAN-MICHEL, BURGER DANIELLE T cell contact-mediated activation of respiratory burst in human polymorphonuclear leukocytes is inhibited by high-density lipoproteins and involves CD18 JOURNAL OF LEUKOCYTE BIOLOGY. 2005 vol. 77 pp. 52-58 CETTOUR ROSE PHILIPPE, NGUYEN TXK, SERRANDER LENA, KAUFMANN MARIE-THÉRÈSE, DAYER JEAN-MICHEL, BURGER DANIELLE, ROUX-LOMBARD-LATUNE PASCALE Apolipoprotein A-I infiltration in rheumatoid arthritis synovial tissue: a control mechanism of cytokine production? ARTHRITIS RESEARCH & THERAPY 2004 vol. 6 pp. 563-566 BRESNIHAN B, GOGARTY M, FITZGERALD O, DAYER JM, BURGER D The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes ARTHRITIS RESEARCH & THERAPY 2004 vol. 6 pp. 181-189 PALMER G, BURGER D, MEZIN F, MAGNE D, GABAY C, DAYER JM, GUERNE PA Cell-cell interactions and tissue damage in rheumatoid arthritis AUTOIMMUNITY REVIEWS 2004 vol. 3 suppl. 1 pp. 7-73 DAYER JM, BURGER D Adrenal insufficiency: the link between low apolipoprotein A-I levels and poor outcome in the critically ill? CRITICAL CARE MEDICINE 2004 vol. 32 pp. 1978-1979 CHENAUD CATHERINE, MERLANI PAOLO, ROUX-LOMBARD-LATUNE PASCALE, BURGER DANIELLE, HARBARTH STEPHAN, LUYASU SAMUEL, GRAF JEAN-DANIEL, DAYER JEAN-MICHEL, RICOU BARA Low apolipoprotein A-I level at intensive care unit admission and systemic inflammatory response syndrome exacerbation CRITICAL CARE MEDICINE 2004 vol. 32 pp. 632-637 CHENAUD C, MERLANI P, ROUX LOMBARD P, BURGER D, HARBARTH S, LUYASU S, GRAF JD, DAYER JM, RICOU B Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease. JOURNAL OF AUTOIMMUNITY 2004 vol. 23 pp. 353-360 VUILLEUMIER NICOLAS, REBER GUIDO, JAMES RICHARD, BURGER DANIELLE, DE MOERLOOSE PHILIPPE, DAYER JEAN-MICHEL, ROUX-LOMBARD-LATUNE PASCALE Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the production of IL-1 receptor antagonist by human adipose tissue JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM 2004 vol. 89 pp. 2652-2658 JUGE-AUBRY CE, SOMM E, CHICHEPORTICHE R, BURGER D, PERNIN A, PITTET-CUENOD B, QUINODOZ P, GIUSTI V, DAYER JM, MEIER CA Differential induction of IL-1 beta and TNF by CD40 ligand or cellular contact with stimulated T cells depends on the maturation stage of human monocytes JOURNAL OF IMMUNOLOGY 2004 vol. 173 pp. 1292-1297 BURGER D, MOLNARFI N, GRUAZ L, DAYER JM Opposite effects of IFN-beta on cytokine homeostasis in LPS- and T cell contact-activated human monocytes JOURNAL OF NEUROIMMUNOLOGY. 2004 vol. 146 pp. 76-83 MOLNARFI N, GRUAZ L, DAYER JM, BURGER D Research's domains