CCR2 and CCR5 chemokine receptors differentially influence the development of autoimmune diabetes in the NOD mouse
ABSTRACT The infiltration of monocytes represents an important early event in the development of autoimmune diabetes in NOD mice. Given that chemokines are key regulators of leukocyte trafficking, we examined the requirement for the chemokine receptors beta(CC)-chemokine receptor-5 (CCR5) and beta(CC)-chemokine receptor-2 (CCR2), which recruit monocytes, in disease development in the NOD mouse. Whereas the onset of diabetes was significantly delayed in CCR2-/-NOD mice (25% at 30 weeks) compared to NOD mice (50% at 28 weeks), the pathogenesis of diabetes was accelerated in CCR5-/-NOD mice (75% at 23 weeks). The rapid development of diabetes in CCR5-/-NOD mice was associated with aggressive destructive insulitis and was accompanied by altered leukocyte migration into islets. In contrast, CCR2-/- NOD mice exhibited delayed inflammatory cell recruitment. Nevertheless, total diabetogenic splenocytes from CCR2-/-NOD and CCR5-/-NOD showed similar capability to adoptively transfer diabetes into NOD.scid recipients. Importantly, our data suggest that targeting of CCR2 may lead to therapies against Type 1 diabetes.
- SourceAvailable from: Alia M. Aldahlawi
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- "). In addition, CCR5 has been reported to directly regulate T-cell function in autoimmune diseases, including MS and RA (Solomon et al., 2010). "
ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation triggered by infiltrating CD4 lymphocytes. The positioning and activation of lympho-cyte in inflamed synovial tissues are dependent on a number of factors including their chemokine receptor expression profile. We aimed to investigate which chemokine receptors pattern correlate with serum cytokine levels and with disease activity. Forty patients with RA (34 female and 6 male) with age range from 21 to 68 years were included. Twenty healthy volunteers (16 female and 4 male) with matched age (range 21–48 years) were served as healthy controls (HCs). Expression of chemo-kine receptors (CCR5, CX3CR1 and CCR7) together with the apoptosis-related marker (CD95) was analyzed using three-color flow cytometry analysis after gating on CD4 + peripheral blood lym-phocytes. Plasma levels of IL-6, IL-10, IL-12 and TNF-a cytokines were measured in all participants using ELISA. Disease activity score (DAS28-CRP) system was assessed and active disease was defined as DAS28 P3.2. Twenty-five (62.4%) patients were classified as active RA (ARA) and 15 (37.5%) patients with inactive RA (IRA). Percentages of CD4 + lymphocytes
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- "One of the primary signals leading to immune cell infiltration into tissues, including the pancreatic islets, is the release of chemotactic cytokines, usually referred to as chemokines , . Synthesis and secretion of chemokines from the β-cell population is a major signal for islet immune cell invasion , ,  and chemokines are critical factors associated with the development of autoimmune diabetes , , , . "
ABSTRACT: Release of pro-inflammatory cytokines from both resident and invading leukocytes within the pancreatic islets impacts the development of Type 1 diabetes mellitus. Synthesis and secretion of the chemokine CCL2 from pancreatic β-cells in response to pro-inflammatory signaling pathways influences immune cell recruitment into the pancreatic islets. Therefore, we investigated the positive and negative regulatory components controlling expression of the CCL2 gene using isolated rat islets and INS-1-derived β-cell lines. We discovered that activation of the CCL2 gene by IL-1β required the p65 subunit of NF-κB and was dependent on genomic response elements located in the -3.6 kb region of the proximal gene promoter. CCL2 gene transcription in response to IL-1β was blocked by pharmacological inhibition of the IKKβ and p38 MAPK pathways. The IL-1β-mediated increase in CCL2 secretion was also impaired by p38 MAPK inhibition and by glucocorticoids. Moreover, multiple synthetic glucocorticoids inhibited the IL-1β-stimulated induction of the CCL2 gene. Induction of the MAP Kinase Phosphatase-1 (MKP-1) gene by glucocorticoids or by adenoviral-mediated overexpression decreased p38 MAPK phosphorylation, which diminished CCL2 gene expression, promoter activity, and release of CCL2 protein. We conclude that glucocorticoid-mediated repression of IL-1β-induced CCL2 gene transcription and protein secretion occurs in part through the upregulation of the MKP-1 gene and subsequent deactivation of the p38 MAPK. Furthermore, the anti-inflammatory actions observed with MKP-1 overexpression were obtained without suppressing glucose-stimulated insulin secretion. Thus, MKP-1 is a possible target for anti-inflammatory therapeutic intervention with preservation of β-cell function.PLoS ONE 10/2012; 7(10):e46986. DOI:10.1371/journal.pone.0046986 · 3.23 Impact Factor
Conference Paper: A new linear, quasicyclic multiple insertion/deletion correcting code[Show abstract] [Hide abstract]
ABSTRACT: A new binary, block-coding scheme for the correction of multiple insertion/deletion errors is presented. This coding scheme is based on similar theory to cyclic codes. A generator polynomial g(X) is used to generate a codebook Q. Constraints on valid generator polynomials are identified and an example of a generator polynomial is given.Communications, Computers and signal Processing, 2003. PACRIM. 2003 IEEE Pacific Rim Conference on; 09/2003