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PubMed2006

CD16+ monocyte-derived macrophages activate resting T cells for HIV infection by producing CCR3 and CCR4 ligands.

The CD16(+) monocyte (Mo) subset produces proinflammatory cytokines and is expanded in peripheral blood during progression to AIDS, but its contribution to HIV pathogenesis is unclear. In this study, we investigate the capacity of human CD16(+) and CD16(-) Mo subsets to render resting CD4(+) T cells permissive for HIV replication. We demonstrate that CD16(+) Mo preferentially differentiate into macrophages (Mphi) that activate resting T cells for productive HIV infection by producing the CCR3 and CCR4 ligands CCL24, CCL2, CCL22, and CCL17. CD16(+), but not CD16(-), Mo-derived Mphi from HIV-infected and -uninfected individuals constitutively produce CCL24 and CCL2. Furthermore, these chemokines stimulate HIV replication in CD16(-) Mo:T cell cocultures. Engagement of CCR3 and CCR4 by CCL24 and CCL2, respectively, along with stimulation via CD3/CD28, renders T cells highly permissive for productive HIV infection. Moreover, HIV replicates preferentially in CCR3(+) and CCR4(+) T cells. These findings reveal a new pathway of T cell costimulation for increased susceptibility to HIV infection via engagement of CCR3 and CCR4 by chemokines constitutively produced by CD16(+) Mo/Mphi. Thus, expansion of CD16(+) Mo in peripheral blood of HIV-infected patients and their subsequent recruitment into tissues may contribute to chronic immune activation and establishment of viral reservoirs in resting T cells.

Antigens, CD↗

PubMed2006

Fatal recall responses mediated by CD8 T cells during intracellular bacterial challenge infection.

The roles(s) of CD8 T cells during infections by intracellular bacteria that reside in host cell endocytic compartments are not well understood. Our previous studies in a mouse model of human monocytotropic ehrlichiosis indicated that CD8 T cells are not essential for immunity. However, we have observed an unexpected role for these cells during challenge infection. Although immunocompetent mice cleared a primary low-dose (nonfatal) Ixodes ovatus ehrlichia infection, a secondary low-dose challenge infection resulted in fatal disease and loss of control of infection. The outcome was CD8-dependent, because CD8-deficient mice survived secondary low-dose challenge infection. Moreover, effector and/or memory phenotype CD8 T cells were responsible, because adoptive transfer of purified CD44(high) CD8 T cells to naive mice induced fatal responses following a primary low-dose infection. The fatal responses were perforin- and Fas ligand-independent, and were associated with high serum concentrations of TNF-alpha and CCL2, and low levels of IL-10. Accordingly, blockade of either TNF-alpha or CCL2 ameliorated fatal recall responses, and in vitro coculture of memory CD8 T cells and Ixodes ovatus ehrlichia-infected peritoneal exudate cells resulted in substantial increases in TNF-alpha and CCL2. Thus, during monocytotropic ehrlichiosis, inflammatory cytokine production, by CD8 T cells and/or other host cells, can trigger chemokine-dependent disease. These findings highlight a novel role for CD8 T cells, and reveal that live vaccines for intracellular bacteria can, under some conditions, induce undesirable consequences.

Adoptive Transfer↗

PubMed2006

Gene expression profile of multiple myeloma cell line treated by realgar.

In order to elucidate the molecular mechanism of Realgar treatment for multiple myeloma (MM), cDNA microaaray was used to compare the gene expression profiles of MM cell line RPMI8226 at 72 hrs pre- and post-Realgar treatment on three separate days. 54 up-regulated and 60 down-regulated genes were identified by cDNA microarray. Further analysis screened out 17 up-regulated and 3 down-regulated genes with Z-score greater than 2 or less than -2, which can be considered the significantly altered genes after Realgar treatment in this study. CCL2, CCL3, BTG1,TNFAIP3, TNFAIP8, SLC38A2, IGFBP4 were important up-regulated genes and they were associated with a variety of cell life functions such as cell growth, cell-cell signaling, regulation of apoptosis and cell homeostasis based on biological process of gene. There are only 3 significantly down-regulated genes (Z-score <-2.0) involved in muscle contract. Several of these genes have been previously identified in relation to MM in published papers. Subsequent validation of selected genes (CCL2, TNFAIP3 and BTG1) by reverse transcription polymerase chain reaction was consistent with our microarray analysis. CCL2 may be involved in MM pathobiology by tumor growth suppression. BTG1 could be used as a potential treatment-related biomarker for monitoring the therapy effect and the remission status of leukemia patients.

Arsenicals↗

PubMed1977

[Metabolism of m-xylene in rats after administration of chlorinated hydrocarbons (author's transl)].

Male albino rats of the Donryu strain were divided into 4 groups: the normal control group, tetrachloromethane (CCl4, TCM) group, tetrachloroethylene (CCl2 = CCl2, PCE) group and trichloroethylene (CHCl = CCl2, TCE) group. Each group was consisted of 6 animals. TCM, PCE and TCE were administered orally at a dosage of 13 mmoles/kg as a 50% v/v olive oil solution to rats 24 hours prior to an oral administration of m-xylene (8.2 mmoles/kg as a 50% v/v olive oil solution). The normal control group was administered only olive oil (2.5 ml/kg) 24 hours prior to m-xylene dose. Urine was collected 24, 48, 72 and 96 hours after administration of m-xylene. The urine was analysed for m-methylhippuric acid (m-MHA) by the paper chromatographic method of Ogata et al. The results obtained were as follows: 1) Total urinary excretion of m-MHA in the normal control group was equivalent on a molar basis to about 58% of m-xylene received, and the major portions of the metabolites were excreted on the 1st day. 2) In TCM group, total urinary excretion of m-MHA was about a half of that in the normal control group. It was equivalent on a molar basis to about 30% of m-xylene received (p less than 0.01), and the urinary excretion of m-MHA on the 1st day was significantly less than those of the normal control group (p less than 0.001) and TCE group (p less than 0.05). 3) In PCE group, urinary excretion of m-MHA on the 1st day was significantly less than that of the normal control group (p less than 0.01) and the excretion was delayed. 4) In TCE group, total urinary excretion of m-MHA was slightly but not significantly less than that of the normal control group (p less than 0.05). 5) In TCM-ip group of rats which were given TCM orally 24 hours prior to the administration of m-xylene by intraperitoneal injection, urinary excretion of m-MHA on the 1st day and in 4 days after administration of m-xylene was less than that of the control-ip group.

Administration, Oral↗

PubMed2006

Sequential patterns of chemokine- and chemokine receptor-synthesis following vessel wall injury in porcine coronary arteries.

Inflammation plays a central role in vascular repair, and spreads into perivascular tissue (PVT) following angioplasty. Chemokines (CK) and chemokine receptors (CKR) are key determinants of inflammatory chemotaxis. We sought to assess the arterial and perivascular expression of the CK CCL2 and CXCL2, and the CKR CCR2, CCR5, and CXCR4 in balloon-injured porcine coronary arteries. Vascular cells that express specific CK and CKR mRNA during post-angioplasty time course were detected by in situ hybridization (ISH), and expression was quantified by real time RT-PCR in PVT. CCL2 was maximal in PVT from 2 to 24h post injury, coincident with local macrophage-activation. Expression was upregulated in media and adventitia from 24h to 3 days, and in neointima at 7 days. CXCL2 was detected in media at 2 and 4h, and also in some neointimal cells. CCR2 and CCR5 were maximal in PVT at 24h and 3 days, respectively. Expression shifted to media and adventitia at 2 and 3 days, and to neointima and adventitia at 7 days, and was low at 14 days. CXCR4 was low in PVT, but was upregulated in media and adventitia at 2 and 3 days, as well as in neointima and adventitia at 7 days. In conclusion, PVT is the primary source of inflammatory CK and CKR early post-angioplasty. Specific sequential patterns of CK- and CKR-synthesis are identified that may regulate phase-specific chemotaxis by spatio-temporally differential expression during coronary response to injury.

Angioplasty, Balloon, Coronary↗

PubMed2004

Regulation of chemokine gene expression and secretion in Staphylococcus aureus-infected osteoblasts.

Staphylococcus aureus is the major cause of osteomyelitis or bone infection, leading to major morbidity, often in children. Little is known about immunopathogenesis of osteomyelitis, although uncontrolled inflammation is a major clinical feature. This study investigated effects of dexamethasone, PGE(2) and T(h)2 cytokines, all potential down-regulatory mediators, on control of S. aureus-induced C-X-C (CXCL8, CXCL10) and C-C (CCL5, CCL2) chemokine gene expression and secretion from human osteoblastic MG-63 cells and primary NHOst cells. Chemokine mRNA expression and secretion were reduced 50-75% by dexamethasone, whereas PGE(2) doubled mRNA accumulation, as detected by RNase protection assay and RT-PCR, but decreased chemokine secretion 33-71% (P < 0.05). IL-10 reduced chemokine mRNA accumulation by 20-40% in MG-63 cells. IL-4 and -13 decreased CXCL8 but not CXCL10 gene expression. IL-10 and IL-13 reduced S. aureus-induced osteoblast C-X-C chemokine secretion, whereas IL-4 decreased CXCL8 secretion 2.5-fold and increased CXCL10 secretion 3-fold (all P < 0.05). In contrast, T(h)2 cytokines increased C-C chemokine secretion from MG-63 osteoblastic cells (P < 0.05), and IL-4 and IL-13 caused similar up-regulation of CCL2 secretion from primary osteoblasts. In summary, during S. aureus infection of osteoblasts, T(h)2 cytokines, dexamethasone and PGE(2) have diverse, sometime upregulatory actions on C-C and C-X-C chemokines due to both pre- and post-transcriptional effects on chemokine secretion.

Cell Line↗

PubMed2004

Recombinant respiratory syncytial virus lacking secreted glycoprotein G is attenuated, non-pathogenic but induces protective immunity.

Respiratory syncytial virus (RSV) causes intense pulmonary inflammatory responses in some infected infants. The surface attachment protein 'G' of RSV has membrane-bound and secreted forms and shows homology to the CX3C chemokine fractalkine. Using recombinant techniques, we generated replication-competent recombinant clonal RSV expressing normal G proteins ('rRSV') or only the membrane-bound form of G ('Gmem rRSV'). Both recombinants grew well in HEp-2 cells, but after primary intranasal infection in mice, pulmonary Gmem rRSV replication was reduced tenfold compared to parental or rRSV; moreover, CCL2 and CCL5 production was greatly reduced and no apparent disease or pulmonary cellular infiltration was observed. However, Gmem rRSV-infected mice developed good antibody responses and were fully protected against subsequent intranasal challenge with parental virus. Even in mice sensitized to G by cutaneous infection with recombinant vaccinia expressing G, intranasal challenge with Gmem rRSV caused insignificant disease. We conclude that secreted G is a key viral product assisting virus replication in vivo, enhancing CCL2 and CCL5 production and promoting illness. Engineered RSV mutants lacking the ability to secrete G are thus promising vaccine candidates.

Animals↗

PubMed2006

Neurocysticercal antigens stimulate chemokine secretion from human monocytes via an NF-kappaB-dependent pathway.

Neurocysticercosis, infection with larval Taenia solium, is a common, serious neuroparasitic infection. Larval degeneration results in inflammatory cell influx and granuloma formation which leads to clinical symptomatology. The role of chemokines in such cell influx is unknown. We demonstrate that monocyte stimulation by T. solium larval antigen (TsAg) results in a differential profile of CXCL8/IL-8 (146.5+/-8.5ng/ml after 24h), CCL2/MCP-1 (267+/-4 ng/ml after 48 h) and CCL3/MIP-1alpha (1.72+/-0.43 ng/ml after 8 h) secretion. There was coordinate mRNA accumulation reaching maximum at 1h for CCL3 and 2 h for CXCL8 and CCL2. TsAg induced maximal nuclear binding of p65, p50 and c-rel subunits of the transcriptional regulator NF-kappaB by 2 h. IkappaBalpha but not IkappaBbeta was degraded within 10 min before resynthesis by 2 h. Pre-treatment with the broad-spectrum NF-kappaB inhibitor pyrrolidine dithiocarbamate caused complete abrogation of TsAg-induced CCL2 secretion (p=0.005) and 91% reduction of CXCL8 secretion (p=0.0003). TsAg was unable to induce CXCL8 promoter activity in Toll-like receptor (TLR)-2 or TLR-4/MD-2 transfected HeLa cells in the absence of lectins or other adaptor molecules. In summary, our data demonstrate that TsAg induces chemokine secretion via specific pathways dependent on NF-kappaB but not TLR-4/TLR-2, and indicate a potential mechanism whereby larval degeneration results in brain inflammation.

Animals↗

PubMed2005

Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice.

An increase in fat mass associated with obesity results from recruitment and differentiation of adipocyte progenitor cells. The precise origin of these cells is unknown, although accumulating evidence suggests that circulating stem cells can differentiate into cells of mesenchymal lineage. It is currently unclear whether a progenitor adipocyte population exists in circulation. One potential candidate is the fibrocyte, which may represent a common progenitor cell for several mesenchymal lineages. We demonstrate that these circulating progenitors become adipocytes when cultured under adipogenic conditions, with intracellular lipids accumulation and up-regulation of proteins specific for adipocyte differentiation, including leptin, PPARgamma, and FABP4. cDNA microarray analysis revealed gene clusters that were differentially regulated during adipogenesis of fibrocytes, which were similar to visceral and subcutaneous adipose tissue preadipocyte-to-adipocyte differentiation. Moreover, these progenitors engrafted and formed human adipose tissue following injection into SCID mice. Although fibrocytes express an array of chemokine receptors, we observed an up-regulation of CCR2 expression following fibrocytes differentiation into adipocytes, which was associated with increased chemotactic response to CCL2. This paradigm supports the notion that elevated CCL2 levels in visceral adipose tissue associated with Metabolic Syndrome is a chemotactic niche, whereby fibrocytes can home to and differentiate into adipocytes to perpetuate its tissue formation.

Adipocytes↗

PubMed2006

Levels of serum chemokines discriminate clinical myelopathy associated with human T lymphotropic virus type 1 (HTLV-1)/tropical spastic paraparesis (HAM/TSP) disease from HTLV-1 carrier state.

Approximately 5% of people infected with human T lymphotropic virus type 1 (HTLV-1) develop clinical myelopathy or tropical spastic paraparesis (HAM/TSP) that is associated with high-levels of Th1 cytokines, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. Chemokines are known to induce cytokine secretion and direct the trafficking of immune cells to sites of disease. The present study measured serum chemokines correlated with autonomously released IFN-gamma in cell cultures. HTLV-1 infection was defined by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot. Subjects included HTLV-1 carriers (n = 56), patients with HAM/TSP (n = 31) and healthy HTLV-1 seronegative volunteer controls (n = 20). Serum chemokines and IFN-gamma autonomously released by mononuclear cells in culture were quantified by ELISA. Compared to HTLV-1 carriers, serum chemokines in HAM/TSP patients showed significantly increased levels of CXCL9 and CXCL10, significantly diminished levels of CCL2 and similar amounts of CCL11 and CCL24. In contrast, CCL11 and CCL24 were significantly lower in serum of HAM/TSP patients than either control. IFN-gamma was positively correlated with CXCL9 and CXCL10 when HAM/TSP and HTLV-1 carriers were used as a combined group. However, despite a large proportion of HTLV-1 carriers having high IFN-gamma levels, these chemokines were not increased in carriers. This study showed that high levels of CXCL9 and CXCL10 in the systemic circulation and low serum CCL2 levels are features of HAM/TSP. HTLV-1 infection and Tax and/or additional viral encoded factor-mediated pathological processes triggering T cell activation with autogenous IFN-gamma release are probably involved in regulating chemokine release.

Biomarkers↗

PubMed2004

Chemokine gene polymorphisms associate with gender in patients with uveitis.

Uveitis is an inflammatory condition of ocular tissue characterized by leukocyte infiltration, tissue damage, and decreased visual acuity. Chemokines have been implicated in the pathogenesis of uveitis. Polymorphisms in the genes encoding chemokines have been described as affecting chemokine production or function. We analyzed the frequency of single-nucleotide polymorphisms (SNPs) in genes encoding CCL2 (-2518 and -2076) and CCL5 (-403 and -28) in patients with Behçet's disease (BD), a systemic form of uveitis, and patients with retinal vasculitis (RV), an organ-specific form of disease. We report that there was no association between any SNP and disease. However, when segregated on the basis of gender the CCR5 -403 AA genotype was only found in male patients with BD. Similarly, CCL2 genotypes 1/2 were predominant in males, while genotype 4 was significantly associated with disease in female patients with BD. Differences in disease symptoms and severity between males and females have been described in BD and gender-specific genetic differences in chemokine gene function may be involved.

Behcet Syndrome↗

PubMed2006

Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus.

AIMS: The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines. SUBJECTS AND METHODS: Forty-two non-diabetic first-degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA-2 antibody). Follow-up for 9-11 years confirmed high vs. moderate diabetes risk in islet autoantibody-positive vs. -negative relatives. Cytokines and chemokines were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum concentrations of classic Th1-associated cytokines (IFN-gamma, IL-12, IL-18) or Th2/Treg-associated cytokines (IL-5, IL-10, IL-13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody-positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody-negative group. CONCLUSION: Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.

Autoantibodies↗

PubMed2004

A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer.

PURPOSE: Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. EXPERIMENTAL DESIGN: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. RESULTS: Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). CONCLUSIONS: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.

Adult↗

PubMed2006

Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium.

Epidemiologic studies implicate inflammatory stimuli in the development of ovarian cancer. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and both its receptors (TNFRI and TNFRII) are expressed in biopsies of this malignancy. Here, we tested the hypothesis that TNF-alpha is a regulator of the proinflammatory microenvironment of ovarian cancer. A cancer profiling array showed higher expression of TNF-alpha in ovarian tumors compared with normal ovarian tissue, and cultured ovarian cancer cells expressed up to 1,000 times more TNF-alpha mRNA than cultured normal ovarian surface epithelial cells; TNF-alpha protein was only detected in the supernatant of tumor cell cultures. Treatment with TNF-alpha induced TNF-alpha mRNA via TNFRI in both malignant and normal cells with evidence for enhanced TNF-alpha mRNA stability in tumor cells. TNF-alpha induced TNF-alpha protein in an autocrine fashion in tumor but not in normal ovarian surface epithelial cells. The TNF-alpha neutralizing antibody infliximab reduced the constitutive levels of TNF-alpha mRNA in tumor cell lines capable of autocrine TNF-alpha production. Apart from TNF-alpha mRNA expression, several other proinflammatory cytokines were constitutively expressed in malignant and normal ovarian surface epithelial cells, including interleukin (IL)-1alpha, IL-6, CCL2, CXCL8, and M-CSF. TNF-alpha treatment further induced these cytokines with de novo transcription of IL-6 mRNA contrasting with the increased stability of CCL2 mRNA. RNA interference directed against TNF-alpha was highly effective in abolishing constitutive IL-6 production by ovarian tumor cells. In summary, we show that TNF-alpha is differentially regulated in ovarian cancer cells compared with untransformed cells and modulates production of several cytokines that may promote ovarian tumorigenesis. Infliximab treatment may have a role in suppressing the TNF-alpha-driven inflammatory response associated with ovarian cancer.

Antibodies, Monoclonal↗

PubMed2005

Exacerbation of retinal degeneration and choroidal neovascularization induced by subretinal injection of Matrigel in CCL2/MCP-1-deficient mice.

This study presents a mouse model for human age-related macular degeneration (AMD) as characterized by subretinal deposit and choroidal neovascularization. Matrigel, a basement membrane extract, solidifies after implantation in tissue and can stimulate local angiogenesis. This study demonstrates the induction of neovascularization and focal retinal degeneration following subretinal Matrigel injection in mice. In senescent mice, the normal functioning of CC chemokine CCL2/MCP-1 and its receptor CCR2 confers protection against age-related retinal degeneration, a disease that shares many similar features with human AMD. Our data shows that CCL2-deficient mice develop more severe disease as compared to the wild-type controls. These findings suggest that Matrigel subretinal injection could be used to generate AMD-like pathological changes. The data support the previously proposed role of CCL2 in AMD pathogenesis.

Animals↗

PubMed2006

Elevated serum levels of CXCL9/monokine induced by interferon-gamma and CXCL10/interferon-gamma-inducible protein-10 in ocular sarcoidosis.

PURPOSE: Sarcoidosis is a chronic multisystem granulomatous disorder characterized by an accumulation of activated CD4+ T cells and monocytes/macrophages in involved organs. Chemokines are required for the extravasation of leukocytes to the inflammation site. This study was undertaken to determine which chemokines are augmented in the serum of patients with active ocular sarcoidosis. METHODS: Seventeen patients with diagnosed ocular sarcoidosis, 28 with suspected ocular sarcoidosis, 16 with Behçet's disease, 17 with Vogt-Koyanagi-Harada disease, and 18 healthy subjects were studied. Serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were simultaneously measured by cytometric bead array using flow cytometer. In addition, serum CXCL9 and CXCL10 levels in the patients with diagnosed or suspected ocular sarcoidosis were compared with respect to ocular disease activity, the presence of bilateral hilar lymphadenopathy (BHL), and laboratory data. RESULTS: Serum levels of both CXCL9 and CXCL10 were markedly elevated in the patients with diagnosed or suspected ocular sarcoidosis compared with patients with other types of uveitis and healthy subjects. Although CCL2 and CXCL8 were detected in the serum of all subjects, the levels were extremely low with no significant differences between groups. Elevation of serum CXCL9 and CXCL10 in ocular sarcoidosis correlated significantly with ocular disease activity and ACE (angiotensin converting enzyme) levels and was unrelated to the presence of BHL, erythrocyte sedimentation rate, white blood cell count, serum IgG, or serum lysozyme. CONCLUSIONS: The results demonstrated that serum levels of CXCL9 and CXCL10 were elevated markedly in the patients with ocular sarcoidosis and correlated with ocular disease activity and ACE level.

Adult↗

PubMed2004

Recombinant guinea pig CCL5 (RANTES) differentially modulates cytokine production in alveolar and peritoneal macrophages.

The CC chemokine ligand 5 (CCL5; regulated on activation, normal T expressed and secreted) is known to recruit and activate leukocytes; however, its role in altering the responses of host cells to a subsequent encounter with a microbial pathogen has rarely been studied. Recombinant guinea pig (rgp)CCL5 was prepared, and its influence on peritoneal and alveolar macrophage activation was examined by measuring cytokine and chemokine mRNA expression in cells stimulated with rgpCCL5 alone or exposed to rgpCCL5 prior to lipopolysaccharide (LPS) stimulation. Levels of mRNA for guinea pig tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, CCL2 (monocyte chemoattractant protein-1), and CXC chemokine ligand 8 (IL-8) were analyzed by reverse transcription followed by real-time polymerase chain reaction analysis using SYBR Green. Bioactive TNF-alpha protein concentration was measured using the L929 bioassay. Both macrophage populations displayed significant enhancement of all the genes and TNF-alpha protein levels when stimulated with rgpCCL5, except for CCL2 in alveolar macrophages. When peritoneal or alveolar macrophages were pretreated with rgpCCL5 for 2 h and then exposed to low concentrations of LPS, diminished cytokine and chemokine mRNA levels were apparent at 6 h compared with LPS alone. At the protein level, there was a reduction in TNF-alpha protein at 6 h in the CCL5-pretreated cells compared with LPS alone. These results further support a role for CCL5 in macrophage activation in addition to chemotactic properties and suggest a role in regulating the inflammatory response to LPS in the guinea pig by modulating the production of proinflammatory cytokines by macrophages.

Animals↗

PubMed2005

Toll-like receptor-7 modulates immune complex glomerulonephritis.

Viral infections may trigger immune complex glomerulonephritis via Toll-like receptors (TLR), as certain TLR trigger immunity upon recognition of viral nucleic acids. On the basis of previous findings regarding viral double-stranded RNA and TLR3 in experimental lupus erythematosus, a similar role for TLR7 that recognizes viral single-stranded RNA was hypothesized. Immunostaining of kidney sections of nephritic MRLlpr/lpr mice revealed TLR7 expression in infiltrating ER-HR3-positive macrophages and few CD11c-positive dendritic cells but not in glomerular mesangial cells as observed for TLR3. This finding was consistent with the distribution pattern of intravenously injected single-stranded RNA in nephritic MRLlpr/lpr mice. TLR7 ligation activated monocytes and dendritic cells, both isolated from MRLlpr/lpr mice, to secrete IFN-alpha, IL-12p70, IL-6, and CCL2. In vivo, a single injection of the TLR7 ligand imiquimod increased serum levels of IL-12p70, IFN-alpha, and IL-6. A course of 25 microg of imiquimod given every other day from week 16 to 18 of age aggravated lupus nephritis in MRLlpr/lpr mice. This was associated with increased glomerular immune complex deposits as well as interstitial expression of CCL2 in imiquimod-treated MRLlpr/lpr mice. Different types of viral nucleic acids seem to modulate systemic autoimmunity through specific interactions with their respective TLR. Different TLR expression profiles on immune cell subsets and nonimmune parenchymal cell types determine the molecular mechanisms involved in viral infection-associated exacerbation of lupus nephritis and possibly other types of immune complex glomerulonephritis.

Aminoquinolines↗