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At least 235 records · Page 13Linked to original sources
PubMed2006

A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord.

We examined the role of tumor necrosis factor receptor 1 (TNFR1) in inflammation initiated by the adoptive transfer of central nervous system (CNS)-specific Th1 cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. This adoptive transfer paradigm eliminates the confounding effects of bacterial adjuvants in the analysis of inflammation. We found that although T cells could reach the meninges and perivascular space in the absence of TNFR1, recruitment of other inflammatory cells from the blood was dramatically reduced. The reduction in the recruitment of CD11b(hi) cells correlated with a dramatic reduction in the production of the chemokines CCL2 (MCP-1) and CXLC2 (MIP-2) in TNFR1-deficient hosts. Bone marrow chimera experiments demonstrated that TNF can be effectively supplied by either the hematopoietic system or the CNS, but the essential TNFR1-responsive cells reside in the CNS. Previous work has demonstrated that microglia produce CCL2, and here we demonstrate that astrocytes and endothelial cells produced CXCL2 in the early stages of inflammation. Therefore, productive inflammation results from a conversation, or mutually responding signals, between the initiating T cells and cells in the parenchyma of the spinal cord.

Adoptive Transfer↗
PubMed2003

Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130.

Studies in IL-6-deficient (IL-6(-/-)) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6(-/-) mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.

Animals↗
PubMed2005

Functional characterization of human cysteinyl leukotriene 1 receptor gene structure.

The 5-lipoxygenase pathway has been strongly implicated in the pathogenesis of chronic inflammatory disorders, such as bronchial asthma and atherosclerosis. Cysteinyl leukotrienes (cysLTs), 5-lipoxygenase pathway products, are recognized now not only as important factors in asthmatic inflammation, but also as mediators of cell trafficking and innate immune responses. To study a role of cysLTs in inflammatory reactions we have characterized the gene structure of human cysteinyl leukotriene receptor type I (cysLT(1)R). The cysLT(1)R gene consists of 5 exons that are variably spliced and a single promoter region with multiple transcription start sites. Four different cysLT(1)R transcripts were identified. RT-PCR showed dominant and wide expression of the transcript I, containing exons 1, 4, and 5, with the strongest presence in blood leukocytes, spleen, thymus, lung, and heart. The expression of cysLT(1)R is functionally regulated at the transcriptional level by IL-4 through a STAT6 response element localized to the proximal cysLT(1)R promoter region. IL-4 stimulation increased cysLT(1)R mRNA (real-time PCR) and surface protein expression (flow cytometry) in a time-dependent fashion. CysLTs (LTD(4) and LTC(4)) induced an increased production of a potent monocyte chemoattractant CCL2 (MCP-1) in IL-4-primed THP-1 cells in a dose-dependent manner. This effect was effectively inhibited by the cysLT(1)R-selective antagonist MK571 in a dose-dependent manner and only partially by a nonselective cysLT(1)R/cysLT(2)R inhibitor BAY-u9773, implying a cysLT(1)R-mediated mechanism. Thus, cysLTs signaling through cysLT(1)R might contribute to inflammatory reactions by cooperating with IL-4 in enhanced CCL2 production in human monocytic cells.

Base Sequence↗
PubMed2003

LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo.

There is increasing evidence that chemokines, specialized regulators of the peripheral immune system, are also involved in the physiology and pathology of the CNS. It is known that glial cells (astrocytes and microglia) express various chemokine receptors like CCR1, -3, -5, and CXCR4. We have investigated the possible expression of the known CC chemokine receptors (CCR1-8 and D6) in murine glial cells. In addition, we examined possible glial expression of the orphan CC chemokine receptor L-CCR that has been identified previously in murine macrophages. We report here expression of L-CCR mRNA in murine astrocytes and microglia. Furthermore, L-CCR mRNA expression was strongly induced after application of bacterial lipopolysaccharide (LPS), both in vitro and in vivo. Functional studies and binding experiments using biotinylated monocyte chemoattractant protein (MCP)-1 (CCL2) indicate that CCL2 could be a candidate chemokine ligand for glial L-CCR. Based on the data presented, it is suggested that L-CCR is a functional glial chemokine receptor that is important in neuroimmunology.

Animals↗
PubMed2005

Immunological mechanisms elicited at the tumour site by lymphocyte activation gene-3 (LAG-3) versus IL-12: sharing a common Th1 anti-tumour immune pathway.

The experimentally induced TS/A murine mammary carcinoma is poorly immunogenic and mainly infiltrated by antigen-presenting cells (APCs), namely macrophages and immature dendritic cells (DCs). Human (h) and mouse (m) lymphocyte activation gene-3 (LAG-3 or CD233) is a physiological MHC class II ligand and powerful APC activator. A gene transfer approach has revealed its anti-tumour activity in this model: hLAG-3 was more effective than mLAG-3. To obtain a clearer picture of the immunoregulatory mechanisms associated with the rejection dynamics of h- and m-LAG-3 transfectants, immunohistochemistry and confocal microscopy analyses of TS/A-hLAG-3, TS/A-mLAG-3, and control TS/A-pc tumours were performed. The immune events elicited by mLAG-3 and m-interleukin (IL)-12 were also compared, since their rejection kinetics were quite similar, and LAG-3 enables IL-12 production by macrophages and DCs. Both the TS/A-h- and, to a lesser extent, the m-LAG-3 rejection areas were characterized by an impressive recruitment of APCs, granulocytes, NK cells, CD4+ T lymphocytes and CD8+ IFNgamma-expressing cells. In both cases, infiltration by APCs was accompanied by strong CD80 and CD86 expression and macrophage nitric oxide (NO) synthase up-regulation. Distinct expression of IL-12 and CXCL9 was also found, especially in the draining lymph nodes. T lymphocytes and CD86-expressing APCs were significantly prevalent in both the TS/A-h- and the m-LAG-3 compared with the TS/A-mIL-12 rejection area. Production of IFNgamma, TNFalpha and IL1beta, and chemokines, namely CXCL5, CXCL9, CXCL10, CXCL11, CCL5, and CCL2, by infiltrating leukocytes and signs of defective neovascularization were detected in tumours expressing h-LAG-3-, m-LAG-3-, and m-IL-12. However, IFNgamma, CCL2, and CCL5 production prevailed in the TS/A-hLAG-3 rejection area. Taken together, these results indicate that LAG-3 expression by engineered tumour cells efficiently promotes intra-tumoural recruitment, activation, and Th1 commitment of APCs, and leads to a wide intra-tumoural influx of non-specific and specific reactive cells, and the release of immunoregulatory and cytotoxic mediators. Many of LAG-3's anti-tumour activities are shared with IL-12.

Animals↗
PubMed2006

Gene expression profile of the infective murine model for biliary atresia.

One hypothesis of the pathogenesis of biliary atresia (BA) is a virus-induced and immune-mediated injury to bile duct cells as mimicked in the rotavirus-induced murine model. This theory is supported by studies showing a predominant T helper cell response type 1-like phenotype of inflammation with increased interferon gamma-induced chemokines in the liver of humans and mice suffering from BA. Recent gene expression profiling studies using microarray analysis showed the induction of a proinflammatory state in human liver specimens with high analogies in extrahepatic biliary tissue of BA mice. The aim of the present study was a microarray analysis of gene expression in the liver of Balb/c mice, comparing infected mice that show the phenotype of BA versus infected mice without symptoms, thus trying to elucidate genes that are not related to the viral origin of this model, but to the specific pathogenesis of the clinical picture of BA. Fifteen mug of RNA, each of three BA-positive and three BA-negative mice, were pooled and comparatively hybridized to spotted cDNA microarrays containing 250 key genes with high relevance to immunological settings. We identified the 40 genes most differentially expressed in mice with and without BA. The majority of genes with higher expression in BA-positive mice encoded proinflammatory cytokines involved in the Th1 pathway, such as CCL2, CCL5, CCR5, CXCL10, CCL2, IL1F5 and in apoptosis, such as DDR3 and granzyme A and B. In this initial study of the molecular characterization of our RRV-induced BA mouse model system, we also found potential novel candidates important to BA etiology, such as growth hormone receptor and insulin-like growth factor. Of particular interest, very low expression of TIMD2 was observed in BA-positive mice. TIMD2 plays a critical role in the regulation of a Th2-type response through the inhibition of IFN gamma.

Animals↗
PubMed2026

Revealing the cytokine-mediated embryo-maternal crosstalk during extended in vitro culture in the Arabian camel (Camelus dromedarius).

This study reports, for the first time, the establishment of endometrial organoids (EOs) from the Arabian camel (Camelus dromedarius) and evaluates their suitability as an in vitro model for embryo-maternal interactions during implantation. Endometrial tissues were collected from non-pregnant she-camels and cultured in Matrigel with a defined growth medium. By Day 7, organoids displayed a spherical morphology (200-250 µm), remained viable for up to 20 days, and expanded to approximately 1 mm. They exhibited epithelial characteristics and high proliferative activity, confirmed by expression of mucin-1, pan-cytokeratin, vimentin, and Ki67. Day 7 in vitro-produced embryos co-cultured with EOs showed significant improvements in development and trophoblast outgrowth. This was accompanied by upregulation of key developmental genes (OCT4, c-MYC, KLF4, CDX2). Cytokine profiling revealed enhanced bidirectional signaling: embryos increased secretion of CCL2, CCL4, IGF-1, IFNG, IL1α, IL12b, IL-8, LIF, IL-10, and NTF3, while EOs upregulated VEGFA, IL-8, CCL2, and TIMP1. Co-culture uniquely induced additional cytokines and amplified signaling intensity. Metabolomic analysis of embryo-conditioned medium identified 108 metabolites, including steroids associated with immunomodulation. Notably, embryos cultured in EO-conditioned medium developed up to Day 21 post-cleavage, reaching a mean diameter of 2.4 mm. Overall, camel EOs provide a physiologically relevant platform that supports embryo development and enables detailed investigation of cytokine-mediated embryo-maternal communication and implantation processes in the dromedary camel.

Camel↗
PubMed2026

Myeloma engraftment suppresses osteocytic ossification signatures rescued by loading in mice and reveals predictors of patient outcome.

Multiple myeloma (MM) is a malignant plasma cell disease inducing osteolytic lesions by disrupting bone homeostasis, fostering catabolic and suppressing anabolic functions. While the impact on osteoblast generation and function is well documented, alterations of osteocyte function and extracellular matrix (ECM) are not yet fully understood. Thus, using a syngeneic mouse model of MM by injecting MOPC315.BM cells intratibially into BALB/c mice (n = 95), we performed transcriptomic profiling of an osteocyte-enriched population and identified a mechanosensitive matrisomal gene signature, which was disrupted by tumor engraftment. Non-invasive tibial loading restored the expression of 94 ECM-associated genes, including collagens, fibronectin, and aggrecan. Cross-species integration with RNA-seq data from 387 MM patients revealed eight ECM-related genes whose expression correlated with overall survival (VEGFA, BCAN, FGF13, TNFSF8, SDC1, LAMC1, SEMA3A, and CCL2). Four of these genes (Vegfa, Sdc1, Sema3a, Ccl2) were also load-responsive in a murine osteocyte (IDG-SW3 cells) bioreactor model. Our findings indicate that an existing mechanosensitive osteocytic repair program is suppressed by MM cells, which can be reinvigorated via a brief single loading session. It suggests that exercise-based interventions may be beneficial to restore bone mass through endochondral ossification programs in patients with MM.

Bone disease↗
PubMed2005

Elevated interleukin-12 and CXCL10 in subacute sclerosing panencephalitis.

Immunosuppression associated with measles virus (MV) can be demonstrated by cytokine production failure in subacute sclerosing panencephalitis (SSPE) and may have implications on the pathogenesis of the disease. Cytokines (IL-12, IL-10, IL-4, IL-17, IL-18, IFN-alpha, IFN-gamma) and chemokines (CXCL8, CXCL10, CCL2 and CCL5) were measured in the cerebrospinal fluid (CSF) and serum samples from 60 patients with SSPE, 36 patients with infectious and/or inflammatory (IN) and 28 with other non-inflammatory (NIN) neurological diseases by ELISA. IL-12 p70+p40 was elevated in CSF and sera of SSPE when compared to the NIN group. However, the CSF levels of IL-12 p70 alone were not increased, indicating an increase of p40. The CSF of SSPE patients also showed relatively higher levels of IL-10 than that of the NIN group. CXCL10 levels in CSF were significantly higher in SSPE, whereas CXCL8 was increased in sera compared to NIN. No difference was detected in IFN-gamma, IFN-alpha, IL-17, IL-18, IL-4 or CCL2 and CCL5 levels. These results demonstrate that immune response against MV in SSPE may be impaired, although some T cell/Th1 inducing stimulations are present.

Chemokine CXCL10↗
PubMed2006

Synergistic inhibition in vivo of bone marrow myeloid progenitors by myelosuppressive chemokines and chemokine-accelerated recovery of progenitors after treatment of mice with Ara-C.

OBJECTIVE: Selected chemokines suppress proliferation of hematopoietic progenitor cells (HPCs) in vitro; some of these have demonstrated inhibition of myelopoiesis in vivo. Because myelosuppressive chemokines synergize in vitro with other myelosuppressive chemokines, we sought to determine whether additional chemokines active in vitro were myelosuppressive in vivo and whether combinations of myelosuppressive chemokines synergized in vivo to dampen myelopoiesis. We also evaluated three chemokines in vivo for myeloprotection against Ara-C-induced decreases in HPCs. METHODS: C3H/HeJ mice were used for analysis of in vivo influence of chemokines, with the end points being effects on absolute numbers and cycling status of HPCs. RESULTS: When used alone, CCL2, CCL3, CCL19, CCL20, CXCL4, CXCL5, CXCL8, CXCL9, and XCL1 caused dose-dependent significant decreases in absolute numbers and cycling status of HPCs in vivo. The following combinations of two chemokines resulted in in vivo myelosuppression at concentrations much lower than that induced by each chemokine alone: CCL3 plus either CXCL8 or CXCL4, CXCL8 plus CXCL4, CCL2 plus either CCL20 or CXCL9, CCL20 plus CXCL9, CXCL5 plus either XCL1 or CCL19, XCL1 plus CCL19, and CCL3 plus CCL19. Also, mice injected with CXCL8, CXCL4, or the chimeric CXCL8/CXCL4 protein CXCL8M1 manifested accelerated recovery of absolute numbers of HPCs in response to the toxic effects of Ara-C administration. CONCLUSIONS: A number of chemokines shown previously to manifest inhibitory effects in vitro for proliferation of HPCs are now demonstrated to also induce myelosuppression in vivo. Moreover, combinations of low dosages of two myelosuppressive chemokines when administered together demonstrate synergistic suppression in vivo. Additionally, chemokines, including a CXCL8M1 chimeric protein previously shown to manifest enhanced suppression of HPC proliferation in vitro and in vivo, accelerate HPC recovery after treatment of mice with Ara-C. These results may be of use for future clinical utility of chemokines in a myelosuppressive/myeloprotective setting.

Animals↗
PubMed2006

Expression analysis of immune response genes of Müller cells infected with Toxoplasma gondii.

PURPOSE: To investigate changes in immune response genes following Toxoplasma gondii infection of Müller cells. METHODS: Human Müller cells were infected or mock infected with two strains of T. gondii (RH and Prugniaud). RNA and supernatants were collected from infected and uninfected cells at 2 and 24 h. RNA from the two time points were compared using a custom made DNA microarray. Real time PCR or human cytokine antibody array was used to confirm up-regulation of immune molecules. RESULTS: Gene expression in infected cells showed up-regulation of CCL2, IL-6, CXCL8, and CXCL2. CCL2 and CXCL2 gene expression was confirmed by real time PCR. IL-6 and CXCL8 protein production was confirmed by a cytokine antibody array. IL-4 production was observed by cytokine antibody array but not by DNA microarray. In contrast, infection with T. gondii did not induce interferon-gamma (IFNgamma) and IL-12 expression, molecules conventionally associated with the inter-conversion of tachyzoite to bradyzoite. CONCLUSION: These results indicate that while in vitro infected Müller cells may be capable of inducing an immune response by attracting blood-borne leucocytes, they do not appear able to directly control the proliferation of T. gondii.

Animals↗
PubMed2006

Blockade of endothelin ET(A)/ET(B) receptors favors a role for endothelin during acute Trypanosoma cruzi infection in rats.

Endothelin has been implicated in the pathogenesis of experimental and human Chagas' disease (American trypanosomiasis). In the present study, we tested the effect of bosentan, an antagonist of both ET(A) and ET(B) endothelin receptors, on parasitemia, histopathology (heart and diaphragm), heart levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, interferon (IFN)-gamma, CCL2, CCL3 and CCL5, and the serum levels of nitrate/nitrite (NOx). Bosentan treatment was accompanied by a significant increase in parasitemia and tissue parasitism or inflammation. In vehicle-treated rats, Trypanosoma cruzi infection increased the cardiac levels of TNF-alpha, IFN-gamma and IL-10, at day 9 post inoculation, and the TNF-alpha remained elevated until day 13. The infection also caused a significant increase in the cardiac levels of the chemokines CCL2 (9, 13 and 18 days) and CCL3 (13 and 18 days). Bosentan-treatment had no significant effect on the infection-associated increase in IFN-gamma and chemokine concentrations. There was a lower increase in IL-10 at day 9 and this was mirrored by a greater increase of TNF-alpha at day 13, in comparison with vehicle-treated rats. These latter findings correlated well with the enhanced inflammatory process in hearts of bosentan-treated infected rats. Bosentan treatment reduced the infection-associated increase in NOx serum concentration. Altogether, our data suggest that ET action on ET(A) and ET(B) receptors may play a role in the initial control of T. cruzi infection in rats probably by interfering in NO production.

Animal Structures↗
PubMed2006

Amyloid-beta peptides induce several chemokine mRNA expressions in the primary microglia and Ra2 cell line via the PI3K/Akt and/or ERK pathway.

Alzheimer's disease (AD) is characterized by the presence of senile plaques composed primarily of amyloid-beta peptide (Abeta) in the brain. Microglia have been reported to surround these Abeta plaques, which have opposite roles, provoking a microglia-mediated inflammatory response that contributes to neuronal cell loss or the removal of Abeta and damaged neurons. To perform these tasks microglia migrate to the sites of Abeta secretion. We herein analyzed the process of chemokine expression induced by Abeta stimulation in primary murine microglia and Ra2 microglial cell line. We found that Abeta1-42 induced the expressions of CCL7, CCL2, CCL3, CCL4 and CXCL2 in the microglia. The signal transduction pathway for the expression of CCL2 and CCL7 mRNA induced by Abeta1-42 was found to depend on phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK), whereas the pathway for CCL4 depended only on PI3K/Akt. These inflammatory chemokine expressions by Abeta stimulation emphasize the contribution of neuroinflammatory mechanisms to the pathogenesis of AD.

Amyloid beta-Peptides↗
PubMed2005

Characterization of oak and birch dust-induced expression of cytokines and chemokines in mouse macrophage RAW 264.7 cells.

Occupational exposure to wood dust is related to several respiratory diseases, such as allergic rhinitis, chronic bronchitis, and asthma. However, virtually nothing is known about molecular mechanisms behind wood dust-induced pulmonary inflammation. To elucidate the effects of wood dust exposure on cytokine and chemokine expression in murine macrophage cell line cells, mouse RAW 264.7 cells were exposed to two selected hardwood dusts, oak and birch. TiO2 and LPS were used as controls. Expression patterns of several cytokines, chemokines, and chemokine receptors were assessed by real-time quantitative PCR system and by ELISA. Exposure to birch dust caused a major increase in TNF-alpha and IL-6 protein levels whereas a weaker induction of TNF-alpha protein was found after exposure to oak dust. Inorganic TiO2 dust did not induce significant cytokine expression. With respect to the chemokines, a dose-dependent, about 10-fold induction of CCL2 mRNA and protein was found after exposure to birch dust. Oak dust induced weakly CCL2 protein. Similarly, birch dust induced a strong expression of CCL3, CCL4, and CXCL2/3 mRNA whereas only moderate levels of these chemokine mRNAs were detected after oak dust exposure. In contrast, expression of CCL24 mRNA was inhibited by more than 40-fold by both oak and birch dusts. TiO2 dust induced about five-fold expression of CCL3 and CCL4 mRNA but did not affect significantly other chemokines. These results suggest that exposure to birch or oak dusts may influence the development of the inflammatory process in the airways by modulating the expression of macrophage-derived cytokines and chemokines.

Animals↗
PubMed2006

Extracellular HIV-1 Nef increases migration of monocytes.

Infiltration of human immunodeficiency virus type 1 (HIV-1)-infected and uninfected monocytes/macrophages in organs and tissues is a general phenomenon observed in progression of acquired immunodeficiency syndrome (AIDS). HIV-1 protein Nef is considered as a progression factor in AIDS, and is released from HIV-1-infected cells. Here, we show that extracellular Nef increases migration of monocytes. This effect is (i) concentration-dependent, (ii) reaches the order of magnitude of that induced by formyl-methyonyl-leucyl-proline (fMLP) or CC chemokine ligand 2 (CCL2)/monocyte chemotactic protein (MCP)-1, (iii) inhibited by anti-Nef monoclonal antibodies as well as by heating, and (iv) depends on a concentration gradient of Nef. Further, Nef does not elicit monocytic THP-1 cells to express chemokines such as CCL2, macrophage inhibitory protein-1alpha (CCL3) and macrophage inhibitory protein-1beta (CCL4). These data suggest that extracellular Nef may contribute to disease progression as well as HIV-1 spreading through affecting migration of monocytes.

Cell Movement↗
PubMed2005

CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.

Bone marrow-derived cells are known to play important roles in repair/regeneration of injured tissues, but their roles in pathological fibrosis are less clear. Here, we report a critical role for the chemokine receptor CCR2 in the recruitment and activation of lung fibrocytes (CD45(+), CD13(+), collagen 1(+), CD34(-)). Lung fibrocytes were isolated in significantly greater numbers from airspaces of fluorescein isothiocyanate-injured CCR2(+/+) mice than from CCR2(-/-) mice. Transplant of CCR2(+/+) bone marrow into CCR2(-/-) recipients restored recruitment of lung fibrocytes and susceptibility to fibrosis. Ex vivo PKH-26-labeled CCR2(+/+) lung fibrocytes also migrated to injured airspaces of CCR2(-/-) recipients in vivo. Isolated lung fibrocytes expressed CCR2 and migrated to CCL2, and CCL2 stimulated collagen secretion by lung fibrocytes. Fibrocytes could transition into fibroblasts in vitro, and this transition was associated with loss of CCR2 expression and enhanced production of collagen 1. This is the first report describing expression of CCR2 on lung fibrocytes and demonstrating that CCR2 regulates both recruitment and activation of these cells after respiratory injury.

Animals↗
PubMed2003

Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation.

During inflammatory skin disorders such as psoriasis, atopic dermatitis, and allergic contact dermatitis, epidermal keratinocytes overexpress large amounts of soluble epidermal growth factor receptor ligands in response to tumor necrosis factor alpha and interferon gamma. These cytokines also promote de novo synthesis of numerous chemokines, including CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and CXCL8/IL-8, in turn responsible for the recruitment of different leukocyte populations. This study demonstrates that stimulation of EGFR down-regulates CCL2, CCL5, and CXCL10, while it increases CXCL8 expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, and reduced CXCL8 expression. In a mouse model of contact hypersensitivity, a single topical administration of a selective EGFR kinase blocker before antigen challenge results in a markedly enhanced immune response with increased chemokine expression and heavier inflammatory cell infiltrate. Targeting EGFR on epithelial cells may thus have profound impact on inflammatory and immune responses.

Adult↗
PubMed2003

Persistent over-expression of specific CC class chemokines correlates with macrophage and T-cell recruitment in mdx skeletal muscle.

Prior studies and the efficacy of immunotherapies provide evidence that inflammation is mechanistic in pathogenesis of Duchenne muscular dystrophy. To identify putative pro-inflammatory mechanisms, we evaluated chemokine gene/protein expression patterns in skeletal muscle of mdx mice. By DNA microarray, reverse transcription-polymerase chain reaction, quantitative polymerase chain reaction, and immunoblotting, convergent evidence established the induction of six distinct CC class chemokine ligands in adult MDX: CCL2/MCP-1, CCL5/RANTES, CCL6/mu C10, CCL7/MCP-3, CCL8/MCP-2, and CCL9/MIP-1gamma. CCL receptors, CCR2, CCR1, and CCR5, also showed increased expression in mdx muscle. CCL2 and CCL6 were localized to both monocular cells and muscle fibers, suggesting that dystrophic muscle may contribute toward chemotaxis. Temporal patterns of CCL2 and CCL6 showed early induction and maintained expression in mdx limb muscle. These data raise the possibility that chemokine signaling pathways coordinate a spatially and temporally discrete immune response that may contribute toward muscular dystrophy. The chemokine pro-inflammatory pathways described here in mdx may represent new targets for treatment of Duchenne muscular dystrophy.

Animals↗