Tissue-specific expression of murine IP-10 mRNA following systemic treatment with interferon γ

127

111

We examined the extent to which CXCR3 mediates resistance to dengue infection. Following intracerebral infection with dengue virus, CXCR3-deficient (CXCR3−/−) mice showed significantly higher mortality rates than wild-type (WT) mice; moreover, surviving CXCR3−/− mice, but not WT mice, often developed severe hind-limb paralysis. The brains of CXCR3−/− mice showed higher viral loads than those of WT mice, and quantitative analysis using real-time PCR, flow cytometry, and immunohistochemistry revealed fewer T cells, CD8+ T cells in particular, in the brains of CXCR3−/− mice. This suggests that recruitment of effector T cells to sites of dengue infection was diminished in CXCR3−/− mice, which impaired elimination of the virus from the brain and thus increased the likelihood of paralysis and/or death. These results indicate that CXCR3 plays a protective rather than an immunopathological role in dengue virus infection. In studies to identify critical CXCR3 ligands, CXCL10/IFN-inducible protein 10-deficient (CXCL10/IP-10−/−) mice infected with dengue virus showed a higher mortality rate than that of the CXCR3−/− mice. Although CXCL10/IP-10, CXCL9/monokine induced by IFN-γ, and CXCL11/IFN-inducible T cell α chemoattractant share a single receptor and all three of these chemokines are induced by dengue virus infection, the latter two could not compensate for the absence of CXCL10/IP-10 in this in vivo model. Our results suggest that both CXCR3 and CXCL10/IP-10 contribute to resistance against primary dengue virus infection and that chemokines that are indistinguishable in in vitro assays differ in their activities in vivo.

Section: Discussionsupporting

confidence: 82%

Both CXCR3 and CXCL10/IFN-Inducible Protein 10 Are Required for Resistance to Primary Infection by Dengue Virus

Hsieh

Lai

Chen

et al. 2006

127

111

“…Mouse tissue was homogenized for total RNA extraction by the guanidinium isothiocyanate-CsCl method as described previously (16,17). The levels of cytokine and chemokine mRNA were determined either by Northern hybridization using radiolabeled cDNA fragments as described previously (16,17) or by use of the RiboQuant RPA system (BD PharMingen, San Diego, CA) according to the manufacturer's instructions.…”

Section: Rna Preparation Northern Hybridization and Rnase Protectiomentioning

confidence: 99%

“…The levels of cytokine and chemokine mRNA were determined either by Northern hybridization using radiolabeled cDNA fragments as described previously (16,17) or by use of the RiboQuant RPA system (BD PharMingen, San Diego, CA) according to the manufacturer's instructions. Plasmids containing KC, MIP-2, and GAPDH cDNAs were prepared as described previously (18,19).…”

Section: Rna Preparation Northern Hybridization and Rnase Protectiomentioning

confidence: 99%

Distinct Temporal Patterns of Macrophage-Inflammatory Protein-2 and KC Chemokine Gene Expression in Surgical Injury

Endlich

Armstrong²,

Brodsky

et al. 2002

Self Cite

In the present study the regulation of CXC chemokine expression was evaluated in full-thickness abdominal wounds in mice. During the first 24 h after injury, IL-1αβ, KC, macrophage-inflammatory protein (MIP)-2, and monocyte chemoattractant protein-1 were the predominant cytokines and chemokines produced; TNF-α was not detected. Chemokine mRNA expression and protein secretion occurred in two temporal stages. The first, which reached a maximum at 6 h, was associated with high levels of IL-1α and KC and low levels of MIP-2. This stage could be reproduced by intradermal injection of IL-1α or IL-1β and was partially blocked by injection of neutralizing Ab against IL-1α but not IL-1β. In animals depleted of circulating neutrophils, chemokine expression was reduced by nearly 70% during this stage. In the second stage, which peaked at 24 h after injury, modest but significant levels of IL-1β were detected in association with low levels of KC and high levels of MIP-2. This pattern of chemokine expression could not be mimicked by injection of IL-1α or IL-1β (even with prolonged exposure), although MIP-2 expression could be partially inhibited by intradermal injection of neutralizing Ab against IL-1β. Surprisingly, neutrophil depletion before injury resulted in sustained high levels of both KC and MIP-2 expression. These observations demonstrate that these two closely related chemokines are under distinct regulatory controls in vivo that are likely to reflect the temporally ordered participation of different cell types and/or extracellular stimuli and inhibitors.

“…Because gene expression of these three ELR Ϫ CXC chemokines is induced in tissue-, cell type-, and stimulus-specific fashions (10,(12)(13)(14), the effect of CXCL10 neutralization differs depending on the pathogens or immunogens and the target organs affected. We have shown that CXCL10 is selectively induced in dendritic cells (DCs) in the draining lymph nodes (LNs) to retain Th1 cells, maintaining DC-T cluster formation in acute experimental autoimmune encephalomyelitis (EAE) (15) and heat-killed Propionibacterium acnes-induced hepatitis (16).…”

mentioning

confidence: 99%

CXC Chemokine Ligand 10 Neutralization Suppresses the Occurrence of Diabetes in Nonobese Diabetic Mice through Enhanced β Cell Proliferation without Affecting Insulitis

Morimoto

Yoneyama

Shimada

et al. 2004

Self Cite

We have shown that neutralization of IFN-inducible protein 10/CXCL10, a chemokine for Th1 cells, breaks Th1 retention in the draining lymph nodes, resulting in exacerbation in Th1-dominant autoimmune disease models induced by immunization with external Ags. However, there have been no studies on the role of CXCL10 neutralization in Th1-dominant disease models induced by constitutive intrinsic self Ags. So, we have examined the effect of CXCL10 neutralization using a type 1 diabetes model initiated by developmentally regulated presentation of β cell Ags. CXCL10 neutralization suppressed the occurrence of diabetes after administration with cyclophosphamide in NOD mice, although CXCL10 neutralization did not significantly inhibit insulitis and gave no influence on the trafficking of effector T cells into the islets. Because both CXCL10 and CXCR3 were, unexpectedly, coexpressed on insulin-producing cells, CXCL10 was considered to affect mature and premature β cells in an autocrine and/or paracrine fashion. In fact, CXCL10 neutralization enhanced proliferative response of β cells and resultantly increased β cell mass without inhibiting insulitis. Thus, CXCL10 neutralization can be a new therapeutic target for β cell survival, not only during the early stage of type 1 diabetes, but also after islet transplantation.