- Email: [email protected]
39 Cytokines in Guillain Barre syndrome
246
Abstracts / Cytokine 43 (2008) 243–262
cleavage of c-Jun; however, this effect was not observed with other subunits of AP-1. Together, these results indicate a novel mechanism whereby Leishmania uses its surface protease GP63 to subvert the macrophage AP-1 signalling pathway. doi:10.1016/j.cyto.2008.07.079
39 Cytokines in Guillain Barre syndrome Shripad A. Patil, Arun B. Taly, Department of Neuro-Microbiology and Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India Guillain Barre syndrome is an acute inflammatory demyelinating poly radiculopathy manifesting with areflexic flaccid paralysis. This rare T cell mediated disorder involves peripheral nerves and is characterized by ascending weakness and numbness or tingling sensation in the extremities. The immune complications becomes so severe in some cases that patient needs ventilatory assistance. The immune system starts destroying the own myelin sheath that surrounds the axons of peripheral nerves. There is evidence to suggest preceding viral (CMV) or bacterial (Campylobacter jejuni) infection which changes nature of cells in nervous system so that the immune system reacts them as foreign cells due to antigenic mimicry. Cytokines which are the signaling proteins modulate both innate and adaptive immune response by their autocrine, paracrine or endocrine action. In the present study immune mediated demyelination is evaluated by anti-ganglioside (GM1, GD1a, GD1b, GT1c, and Gal-C) antibodies in the serum of the patients with GBS and compared with cytokines (IL-1, IL-2, IL-4, IL-6, IL-12, TNF-alpha, and IFN-gamma. Eighty-six patients were evaluated for the anti-ganglioside antibodies and cytokines using standard reagents and kits. ELISA was standardized for both the assays. Demyelinating antibodies were noticed to the tune of 80% (Gal-C) in the GBS cases and cytokines were detected to the tune of 75% (IL-6). TNF alpha and gamma IFN levels were noticed in 40% and 33% of the cases, respectively. It is interesting to note that cytokines as well as anti-ganglioside antibodies are increased in GBS cases highlighting the pathophysiological role played by these proteins. Following plasmapheresis, reduction in immunoglobulin levels and clinical improvement of the patient further strengthens the pathophysiological role played by demyelinating antibodies and cytokines in GBS.
41 TL1A-DR3 interactions drive immunopathology mediated by multiple T-cell subsets Richard M. Siegel 1, Erin Kahle 1, Krishika Acharya 1, Ivan Fuss 2, Eddie Wang 3, Francoise Meylan 1, 1 Immune-Mediated Diseases Section, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita`, Rome Italy, 2 Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH Bethesda, MD 20892, USA, 3 School of Medicine, Cardiff University, Wales, UK DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain containing tumor necrosis factor receptor primarily expressed in T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but its function in normal and pathological immune responses has not been clear. Recently, TL1A has been found to be highly expressed in affected organs in Rheumatoid Arthritis and Inflammatory bowel disease, and polymorphisms in TL1A have been linked to inflammatory bowel disease in multiple whole genome association studies. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation, and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, polarization into T helper 1 (Th1), Th2 or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 was required on for immunopathology, local T cell accumulation and cytokine production in experimental autoimmune encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. Transfer experiments showed that DR3 was required on T cells to allow for effector cell accumulation in target organs. To determine the potential of TL1A to drive autoimmune inflammatory disease, we have produced transgenic mice that constitutively express TL1A in dendritic cell or T cell lineages. TL1A transgenic mice uniformly develop spontaneous inflammatory bowel disease, with age of onset and severity dependent on the level of transgene expression. Analysis of cytokines present in the gut of these mice reveals a mixed picture with elevations in cytokines linked to both Th2 and Th17 lineages. These results define TL1A as a cytokine produced by similar cells and stimuli as TNF, yet which acts primarily on T cells. Thus, this cytokinereceptor pair may play a function in adaptive immunity similarly to TNF’s role in the innate immune system as an amplifier of inflammatory responses. As such, TL1A and DR3 constitute exciting new targets for immunotherapy of autoimmune and inflammatory diseases with a T cell component. doi:10.1016/j.cyto.2008.07.082
doi:10.1016/j.cyto.2008.07.080
40 Expression and function of Schlafen-4 in macrophage biology and inflammation Wendy J.M. van Zuijlen 1,4, K. Schroder 1,4, V. Garceau 3,4, M.J. Sweet 1,4, S. Kellie 1,2,4, D.A. Hume 1,3,4, 1 Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld, Australia, 2 School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Qld, Australia, 3 Roslin Institute and Royal School of Veterinary Studies, University of Edinburgh, Roslin, UK, 4 CRC for Chronic Inflammatory Diseases, Parkville, Vic., Australia Macrophages are essential for host defence, but when excessively and persistently activated, these cells are a major contributor to the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Investigating the function of inflammatory genes in macrophages may identify novel therapeutic targets for inflammatory diseases. One family of transcripts that are highly expressed in activated macrophages are members of the Schlafen (Slfn) gene family; a recently identified family whose function is still unknown. This study examined the mRNA expression of Slfn in activated bone marrow-derived macrophages (BMMs) in vitro, and in collagen-induced arthritis (CIA) in vivo. Realtime PCR expression analyses of BMMs stimulated with a variety of Toll-like receptor-agonists revealed that Slfn-4 message was highly induced upon stimulation with lipopolysaccharide (LPS) and double stranded RNA Poly (I:C). This response was ablated in IFNAR / BMMs, thus indicating that LPS induced Slfn-4 mRNA via the action of autocrine Interferon-beta (IFN-b). The mRNA expression of several members of the Slfn family were also elevated in joints of mice with collagen-induced arthritis, with the increase in Slfn-4 being most dramatic. To investigate the function of Slfn-4, we used a novel binary expression based on the c-fms promoter and Gal4, to selectively drive Slfn-4 expression in cells of the mononuclear phagocyte system in vivo. Overexpression of Slfn-4 in vivo resulted in a phenotype that includes extramedullary haematopoiesis and a deficiency in blood monocytes. These results imply that Slfn-4, as an IFN-b-target gene, regulates inflammatory responses by modulating monocyte/macrophage survival and development. Further characterisation of the Slfn-4 over expressing mouse line will be used to assess the function of Slfn-4 in macrophage biology and inflammation, and its potential as a therapeutic target. doi:10.1016/j.cyto.2008.07.081
42 Absence of IL-22 aggravates dextran-sulfate induced colitis Laure Dumoutier, Jean-Christophe Renauld, Ludwig Institute for Cancer Research, Brussels, Belgium IL-22 is an IL-10-related cytokine preferentially produced by Th17 cells and mainly active on hepatocytes, keratinocytes and epithelial cells. Because IL-22 expression is upregulated in patients with Crohn’s disease, we studied the role of IL-22 in a mouse model of colitis induced by DSS treatment. IL-22 expression was upregulated in the colon as soon as 4 days after the initiation of the treatment and peaked after 10 days, correlating with other inflammatory markers. Interestingly, a similar IL-22 induction was observed in T cell-deficient mice, indicating that TH17 cells are not the main source of IL-22 in this model and contrasting with IL-17 expression, which was completely abolished in the absence of T cells. Endogenous IL-22 plays an antiinflammatory role in this model as illustrated by the fact that IL-22 knock-out mice exposed to DSS presented more severe weight loss than wild type mice. At the molecular level, microarray analysis showed that the Reg3b and Pla2g2a genes were strongly upregulated by DSS-treatment in wild type mice but not in IL-22 knockout mice. Similar results were obtained by injecting anti-IL-22 antibodies into wild type mice, and, conversely, IL-22 administration upregulated the expression of these genes. Taken together, our results demonstrate that endogenous IL-22 induced during colitis plays an anti-inflammatory role and specifically regulates the expression of the Reg3b and Pla2g2a genes. doi:10.1016/j.cyto.2008.07.083
43 Adipokines and tumor necrosis factor-a in peripheral arterial occlusive disease Claudia Gherman 1, Adriana Muresan 2, Adriana Filip 2, Anca Cristea 3, Aurel Mironiuc 1, Laura Palcau 1, Diana Sacui 1, 1 Surgical Clinic No. 2, Romania, 2 Departement of Physiology, Romania, 3 Medical Clinic No.1, University of Medicine and Pharmacy ‘‘Iuliu Hatieganu” Cluj-Napoca, Romania This study aimed to examine the plasma levels of adipokines (adiponectin, leptin, and resistin), as well as markers of inflammation: tumor necrosis factor-a (TNF-a) in
Abstracts / Cytokine 43 (2008) 243–262
cleavage of c-Jun; however, this effect was not observed with other subunits of AP-1. Together, these results indicate a novel mechanism whereby Leishmania uses its surface protease GP63 to subvert the macrophage AP-1 signalling pathway. doi:10.1016/j.cyto.2008.07.079
39 Cytokines in Guillain Barre syndrome Shripad A. Patil, Arun B. Taly, Department of Neuro-Microbiology and Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India Guillain Barre syndrome is an acute inflammatory demyelinating poly radiculopathy manifesting with areflexic flaccid paralysis. This rare T cell mediated disorder involves peripheral nerves and is characterized by ascending weakness and numbness or tingling sensation in the extremities. The immune complications becomes so severe in some cases that patient needs ventilatory assistance. The immune system starts destroying the own myelin sheath that surrounds the axons of peripheral nerves. There is evidence to suggest preceding viral (CMV) or bacterial (Campylobacter jejuni) infection which changes nature of cells in nervous system so that the immune system reacts them as foreign cells due to antigenic mimicry. Cytokines which are the signaling proteins modulate both innate and adaptive immune response by their autocrine, paracrine or endocrine action. In the present study immune mediated demyelination is evaluated by anti-ganglioside (GM1, GD1a, GD1b, GT1c, and Gal-C) antibodies in the serum of the patients with GBS and compared with cytokines (IL-1, IL-2, IL-4, IL-6, IL-12, TNF-alpha, and IFN-gamma. Eighty-six patients were evaluated for the anti-ganglioside antibodies and cytokines using standard reagents and kits. ELISA was standardized for both the assays. Demyelinating antibodies were noticed to the tune of 80% (Gal-C) in the GBS cases and cytokines were detected to the tune of 75% (IL-6). TNF alpha and gamma IFN levels were noticed in 40% and 33% of the cases, respectively. It is interesting to note that cytokines as well as anti-ganglioside antibodies are increased in GBS cases highlighting the pathophysiological role played by these proteins. Following plasmapheresis, reduction in immunoglobulin levels and clinical improvement of the patient further strengthens the pathophysiological role played by demyelinating antibodies and cytokines in GBS.
41 TL1A-DR3 interactions drive immunopathology mediated by multiple T-cell subsets Richard M. Siegel 1, Erin Kahle 1, Krishika Acharya 1, Ivan Fuss 2, Eddie Wang 3, Francoise Meylan 1, 1 Immune-Mediated Diseases Section, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita`, Rome Italy, 2 Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH Bethesda, MD 20892, USA, 3 School of Medicine, Cardiff University, Wales, UK DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain containing tumor necrosis factor receptor primarily expressed in T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but its function in normal and pathological immune responses has not been clear. Recently, TL1A has been found to be highly expressed in affected organs in Rheumatoid Arthritis and Inflammatory bowel disease, and polymorphisms in TL1A have been linked to inflammatory bowel disease in multiple whole genome association studies. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation, and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, polarization into T helper 1 (Th1), Th2 or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 was required on for immunopathology, local T cell accumulation and cytokine production in experimental autoimmune encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. Transfer experiments showed that DR3 was required on T cells to allow for effector cell accumulation in target organs. To determine the potential of TL1A to drive autoimmune inflammatory disease, we have produced transgenic mice that constitutively express TL1A in dendritic cell or T cell lineages. TL1A transgenic mice uniformly develop spontaneous inflammatory bowel disease, with age of onset and severity dependent on the level of transgene expression. Analysis of cytokines present in the gut of these mice reveals a mixed picture with elevations in cytokines linked to both Th2 and Th17 lineages. These results define TL1A as a cytokine produced by similar cells and stimuli as TNF, yet which acts primarily on T cells. Thus, this cytokinereceptor pair may play a function in adaptive immunity similarly to TNF’s role in the innate immune system as an amplifier of inflammatory responses. As such, TL1A and DR3 constitute exciting new targets for immunotherapy of autoimmune and inflammatory diseases with a T cell component. doi:10.1016/j.cyto.2008.07.082
doi:10.1016/j.cyto.2008.07.080
40 Expression and function of Schlafen-4 in macrophage biology and inflammation Wendy J.M. van Zuijlen 1,4, K. Schroder 1,4, V. Garceau 3,4, M.J. Sweet 1,4, S. Kellie 1,2,4, D.A. Hume 1,3,4, 1 Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld, Australia, 2 School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Qld, Australia, 3 Roslin Institute and Royal School of Veterinary Studies, University of Edinburgh, Roslin, UK, 4 CRC for Chronic Inflammatory Diseases, Parkville, Vic., Australia Macrophages are essential for host defence, but when excessively and persistently activated, these cells are a major contributor to the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Investigating the function of inflammatory genes in macrophages may identify novel therapeutic targets for inflammatory diseases. One family of transcripts that are highly expressed in activated macrophages are members of the Schlafen (Slfn) gene family; a recently identified family whose function is still unknown. This study examined the mRNA expression of Slfn in activated bone marrow-derived macrophages (BMMs) in vitro, and in collagen-induced arthritis (CIA) in vivo. Realtime PCR expression analyses of BMMs stimulated with a variety of Toll-like receptor-agonists revealed that Slfn-4 message was highly induced upon stimulation with lipopolysaccharide (LPS) and double stranded RNA Poly (I:C). This response was ablated in IFNAR / BMMs, thus indicating that LPS induced Slfn-4 mRNA via the action of autocrine Interferon-beta (IFN-b). The mRNA expression of several members of the Slfn family were also elevated in joints of mice with collagen-induced arthritis, with the increase in Slfn-4 being most dramatic. To investigate the function of Slfn-4, we used a novel binary expression based on the c-fms promoter and Gal4, to selectively drive Slfn-4 expression in cells of the mononuclear phagocyte system in vivo. Overexpression of Slfn-4 in vivo resulted in a phenotype that includes extramedullary haematopoiesis and a deficiency in blood monocytes. These results imply that Slfn-4, as an IFN-b-target gene, regulates inflammatory responses by modulating monocyte/macrophage survival and development. Further characterisation of the Slfn-4 over expressing mouse line will be used to assess the function of Slfn-4 in macrophage biology and inflammation, and its potential as a therapeutic target. doi:10.1016/j.cyto.2008.07.081
42 Absence of IL-22 aggravates dextran-sulfate induced colitis Laure Dumoutier, Jean-Christophe Renauld, Ludwig Institute for Cancer Research, Brussels, Belgium IL-22 is an IL-10-related cytokine preferentially produced by Th17 cells and mainly active on hepatocytes, keratinocytes and epithelial cells. Because IL-22 expression is upregulated in patients with Crohn’s disease, we studied the role of IL-22 in a mouse model of colitis induced by DSS treatment. IL-22 expression was upregulated in the colon as soon as 4 days after the initiation of the treatment and peaked after 10 days, correlating with other inflammatory markers. Interestingly, a similar IL-22 induction was observed in T cell-deficient mice, indicating that TH17 cells are not the main source of IL-22 in this model and contrasting with IL-17 expression, which was completely abolished in the absence of T cells. Endogenous IL-22 plays an antiinflammatory role in this model as illustrated by the fact that IL-22 knock-out mice exposed to DSS presented more severe weight loss than wild type mice. At the molecular level, microarray analysis showed that the Reg3b and Pla2g2a genes were strongly upregulated by DSS-treatment in wild type mice but not in IL-22 knockout mice. Similar results were obtained by injecting anti-IL-22 antibodies into wild type mice, and, conversely, IL-22 administration upregulated the expression of these genes. Taken together, our results demonstrate that endogenous IL-22 induced during colitis plays an anti-inflammatory role and specifically regulates the expression of the Reg3b and Pla2g2a genes. doi:10.1016/j.cyto.2008.07.083
43 Adipokines and tumor necrosis factor-a in peripheral arterial occlusive disease Claudia Gherman 1, Adriana Muresan 2, Adriana Filip 2, Anca Cristea 3, Aurel Mironiuc 1, Laura Palcau 1, Diana Sacui 1, 1 Surgical Clinic No. 2, Romania, 2 Departement of Physiology, Romania, 3 Medical Clinic No.1, University of Medicine and Pharmacy ‘‘Iuliu Hatieganu” Cluj-Napoca, Romania This study aimed to examine the plasma levels of adipokines (adiponectin, leptin, and resistin), as well as markers of inflammation: tumor necrosis factor-a (TNF-a) in