Among CXCR3 Chemokines, IFN-γ-Inducible Protein of 10 kDa (CXC Chemokine Ligand (CXCL) 10) but Not Monokine Induced by IFN-γ (CXCL9) Imprints a Pattern for the Subsequent Development of Autoimmune Disease

Christen, Urs; McGavern, Dorian B.; Luster, Andrew D.; Herrath, Matthias G. von; Oldstone, Michael B. A.

doi:10.4049/jimmunol.171.12.6838

Cited by 178 publications

(230 citation statements)

References 45 publications

(130 reference statements)

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“…Furthermore, it has been shown that IL-17A and IL-17F can induce CXCL10 chemokine expression in lung epithelial cells [43,44]. Production of CXCL10 by pancreatic b-cells could contribute to the recruitment of auto reactive T cells expressing the CXCR3 chemokine receptor as previously shown in several mouse models of type 1 diabetes (T10) [45,46]. Thus, iNKT17 cells might not be involved in the initiation of the insulitis but rather could participate in the exacerbation of -b-cell death and diabetes onset.…”

Section: Discussionmentioning

confidence: 81%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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Section: Discussionmentioning

confidence: 81%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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“…MIP-1α −/− mice, the chemokine that binds to CCR5 [19]. A contribution of CXCR3 as well as CCR4 in autoimmune diabetes or pancreatic infiltration has also been documented [20,40,41]. In recent-onset type 1 diabetes patients, a temporary reduction of peripheral CD3 + /CD4 + T cells expressing T H 1-associated chemokine receptors CXCR3 and CCR5 was demonstrated [42].…”

Section: Discussionmentioning

confidence: 97%

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Halteren¹,

Kardol²,

Mulder³

et al. 2004

Diabetologia

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Aims/hypothesis: An important prerequisite for the initiation of pancreatic islet inflammation is the recruitment of pathogenic T cells. We investigated the in vivo migration patterns of human islet-reactive T cell clones after transfer into compromised hosts. Methods: NOD-scid mice were injected with a mixture of human autoreactive T cells and antigen-presenting cells. Survival and migration of T cells was analysed by fluorescenceactivated cell sorter and immunohistochemical analysis of various tissues.

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“…In a lymphocytic choriomeningitis virus-induced mouse model of autoimmune diabetes, increased expression of CXCR3-binding chemokines was reported as an important early event initiating islet infiltration with immune cells [36]. Cultured human islets have been shown to secrete CXCL10 following enterovirus infection [37].…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

et al. 2010

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Aims/hypothesis Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest antiinflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes. Methods The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines. Results IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1β, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels. Conclusions/interpretation These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

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Among CXCR3 Chemokines, IFN-γ-Inducible Protein of 10 kDa (CXC Chemokine Ligand (CXCL) 10) but Not Monokine Induced by IFN-γ (CXCL9) Imprints a Pattern for the Subsequent Development of Autoimmune Disease

Cited by 178 publications

References 45 publications

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

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