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PubMed2006

Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules.

Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte beta(1) and beta(2) integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-alpha-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical beta(1) and beta(2) integrins but also junctional adhesion molecule pathways.

Animals↗
PubMed2004

Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts.

BACKGROUND: The beta-chemokines MCP-1 (CCL2) and RANTES (CCL5) have been shown to play important roles in acute renal transplant rejection (AR) and chronic allograft nephropathy (CAN). The potential relationship of expression of these chemokines, their chemokine receptors CCR1, CCR2, CCR5, and the cell populations of inflammatory infiltrate, histological and clinical diagnoses were investigated in biopsies at the time of AR and compared with biopsies of CAN. METHODS: In 24 renal transplant biopsies with AR (n = 15) and CAN (n = 9), the expression of MCP-1 and RANTES, their receptors CCR1, CCR2, and CCR5 and the infiltration with monocytes/macrophages and T cells were studied. RESULTS: As previously described, chemokine and chemokine receptor expression was found mainly in mononuclear cells infiltrating the interstitium and glomeruli. In the tubulointerstitial area and glomeruli the expression of MCP-1, RANTES, and their receptors correlated with an infiltration by monocytes/macrophages. Biopsies with CAN revealed a lower expression of MCP-1, RANTES, CCR1, CCR2 and CCR5 in tubulointerstitial cells, and a significantly lower infiltration with MRP14-positive monocytes/macrophages than biopsies with AR. In AR, MCP-1 and CCR1 showed a lower expression compared to RANTES, CCR2, and CCR5. CONCLUSIONS: The positive correlation between chemokines and chemokine receptors and infiltrating leukocytes during acute rejection, the lower but detectable expression of MCP-1, RANTES, CCR1, CCR2 and CCR5 in CAN, and the differences in the quantity of expression between the different chemokines and chemokine receptors point to a complex regulation of chemokine expression in renal allografts. Since chemokines are not only involved in inflammation but also in tissue regeneration, this could have impact on the development of CAN.

Adult↗
PubMedDate not supplied

Potential roles of CCL2/monocyte chemoattractant protein-1 in the pathogenesis of cutaneous sclerosis.

Scleroderma is a connective tissue disease of unknown etiology characterized by the excessive deposition of extracellular matrix in the skin. Cellular infiltrates of certain immune cells and pro-inflammatory mediators are suggested to play a crucial role in cutaneous fibrosis, forming complicated networks between fibroblasts and immune cells and/or cell-cell communications. Tissue-selective trafficking of leukocytes is mediated by combinations of adhesion molecules and chemokines. Although chemokines and their receptors are considered to be mediators of inflammation and fibrosis in scleroderma, their pathophysiological role remains incompletely understood. Recent studies suggest that CCL2/monocyte chemoattractant protein-1 plays an important role in the fibrotic process, including liver fibrosis, pulmonary fibrosis, and scleroderma. This review summarizes recent findings of the potential roles of CCL2 in cutaneous sclerosis in experimental animal models of scleroderma as well as human scleroderma.

Animals↗
PubMedDate not supplied

Chemokines in human colorectal carcinoma.

BACKGROUND: Chemokines (CKs) may promote antitumor immunity in cancer, act as tumor growth factors, influence metastatic spreading or angiogenesis. The purpose of this study was to investigate whether CK expression is altered in colorectal carcinomas compared to normal mucosa and to elucidate its possible clinico-pathological implications. MATERIALS AND METHODS: The levels of CCL2 (MCP-1), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL 1 (GRO-alpha), CXCL 5 (ENA-78) and CXCL 8 (IL-8) were investigated in 10 colorectal carcinomas and their corresponding normal mucosa by the use of ELISA. RESULTS: All CK analyzed, with the exception of CCL5 (RANTES), were expressed at a significantly higher level in malignant tissue. CONCLUSION: Therapeutic studies in colon carcinomas should, therefore, focus more on the neutralization of CKs than on their application.

Adenocarcinoma↗
PubMed2026

Interleukin-1α Mediates Pancreatic Fibroblast Activation, Regulates Immune Cell Recruitment and Fibrosis in Acute and Chronic Pancreatitis.

Pancreatitis is a life-threatening inflammatory disease of the pancreas. The cytokine interleukin-1α has been demonstrated to act as an alarmin released by necrotic cells. In the present study, we investigated the influence of IL-1α on the immune response during acute and chronic pancreatitis. Following tissue injury, pancreatic acinar cells released IL-1α, which activates tissue-resident fibroblasts to differentiate toward a pro-inflammatory phenotype. By secreting chemokines and cytokines such as CXCL5, CCL2, and IL-6, these fibroblasts recruit immune cells to the pancreas. The absence of IL-1α reduces disease severity in acute pancreatitis and chemokine release. Furthermore, IL-1α primes fibroblasts to enhance the production of extracellular matrix-components by the up-regulation of pro-fibrotic receptors such as Il4ra, Il13ra1, and Tgfbr3. Therefore, the deletion of IL-1α significantly reduced the development of tissue fibrosis. A therapeutic blockade of the IL1R1-signaling by i.p. administration of the IL-1-receptor antagonist Anakinra showed the same effect; the severity of acute pancreatitis and fibrogenesis during chronic pancreatitis were reduced. In conclusion, the crosstalk between necrotic acinar cells and fibroblasts mediated by IL-1α plays a crucial role in acute inflammation of the pancreas and fibrogenic signaling. Blockade of IL1R1-signaling by Anakinra is therefore a promising therapeutic intervention for both acute and chronic pancreatitis.

Anakinra↗
PubMed2006

Tissue-specific up-regulation of the proteasome subunit beta5i (LMP7) in Sjögren's syndrome.

OBJECTIVE: Sjögren's syndrome (SS) is characterized by autoimmune infiltration and focal accumulation of lymphocytes in the exocrine glands, with a predominance of CD4-positive T cells. Since these histologic findings are nonspecific, determination of clinical and serologic abnormalities contribute to the diagnosis. The aim of this study was to identify a novel, disease-specific, immunologically relevant marker for SS. METHODS: To analyze disease-related and tissue-specific expression of candidate markers, we examined biopsied minor salivary glands and peripheral blood mononuclear cells from patients with primary and secondary SS (n = 26) as well as from patients with sicca symptoms without autoimmune sialadenitis (n = 15). Expression of the Th1/Th2-related chemokines CCL3 (macrophage inflammatory protein 1alpha) and CCL2 (monocyte chemoattractant protein 1), CXCL7 (neutrophil-activating peptide 2 [NAP-2]), interleukin-1beta, inducible costimulator, and the proteasome subunits alpha3 (C9) and beta5i (LMP7) was analyzed at the messenger RNA (mRNA) level using real-time polymerase chain reaction techniques. Immunohistochemical analysis was used to identify the beta5i (LMP7)-expressing cell populations in minor salivary glands. RESULTS: The expression profiles revealed a significant up-regulation of beta5i (LMP7) exclusively in the salivary glands of SS patients. Immunohistochemistry confirmed expression of the immunoproteasome subunit beta5i (LMP7) within the acinar and ductal epithelial cells. No significant difference in the distinct histologic focus scores was evident for the expression of the markers investigated. In the peripheral blood compartment, the expression of CXCL7 was up-regulated both in primary and in secondary SS. CONCLUSION: Tissue-specific up-regulation of beta5i (LMP7) mRNA was shown to be characteristic of SS, indicating a disease-specific modulation of the proteasome system. Expression of beta5i (LMP7) represents an independent parameter that can be used in addition to the focus score to distinguish SS in biopsied labial salivary glands.

Adult↗
PubMed2006

Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis.

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions. METHODS: Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68+,CD1a- non-Langerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry. RESULTS: In all samples, Ki-67 was undetectable in CD68+ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1beta (MIP-1beta), CCL5/RANTES, CCL20/MIP-3alpha, and CCL19/MIP-3beta, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-gamma-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-gamma, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate. CONCLUSION: Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease.

Alendronate↗
PubMed2003

The ester-bonded palmitoyl side chains of Pam3CysSerLys4 lipopeptide account for its powerful adjuvanticity to HLA class I-restricted CD8+ T lymphocytes.

Molecularly defined adjuvants are urgently required to implement immunization protocols by which CD8+ T cells induction is envisaged. We show here that the synthetic lipopeptide Pam3CysSerLys4 (P3CSK4) strongly enhances the expansion of antigen-specific IFN-gamma+CD8+ cells in vitro. These effects critically depend on the presence of two ester-bonded palmitoylated side chains. In fact, T cell expansion is impaired in the presence of derivatives bearing two non-palmitoylated fatty acid chains, while derivatives with only one amide-bonded palmitoylated residue are completely inactive and behave like the non-lipidated peptide backbone. P3CSK4 is not mitogenic for T lymphocytes and can modulate DC immune biological properties. Indeed, doses as low as 100 ng/ml increase CD86, CD83 and CD40 surface expression on DC, fail to induce CCR7, and trigger a defined pattern of soluble factors associated to immune effector functions. In particular, substantial amounts of TNF-alpha, IL-6, CCL2 and CXCL10, in the absence of IFN-alpha, IFN-gamma, IL-15, IL-12p70 and CX3CL1, can be measured. Accordingly, antigen-specific CD8+ T cells expanded in vitro express CCR2 and CXCR3 chemokine receptors. Altogether our data suggest that human DC are able to respond to chemically different synthetic lipopeptide analogs and that optimal adjuvanticity to CD8+ T cell induction is achieved by the palmitoylated structures.

Adjuvants, Immunologic↗
PubMed2004

CC chemokine receptor 2 regulates leukocyte recruitment and IL-10 production during acute polymicrobial sepsis.

Chemokine receptors are important for recruiting leukocytes to sites of infection and may contribute to immune cell activation. The present study investigated the role of the chemokine receptor CCR2 in polymicrobial septic peritonitis. The results showed that peritoneal production of the CCR2 ligands CCL2 and CCL12 in septic mice was largely independent of the common Toll-like receptor signaling adaptor MyD88. Antibody blockade of CCR2 reduced the recruitment of macrophages and neutrophils to the infected peritoneal cavities of both wild-type and MyD88-deficient mice, suggesting that CCR2 engagement contributes to the MyD88-independent cellular response against polymicrobial septic peritonitis. Notably, administration of blocking CCR2 antibodies markedly increased local and systemic IL-10 levels in septic wild-type mice, whereas IL-10 was not detected in MyD88-deficient mice irrespective of whether CCR2 was blocked or not. Inhibition of CCR2 directly augmented Toll-like receptor-induced IL-10, but not TNF and IL-6, production of macrophages in vitro. Concomitant with enhanced IL-10 production, CCR2 blockade caused impaired bacterial clearance and aggravated kidney injury in wild-type, but not MyD88-null mice. These results indicate that CCR2 engagement modulates the innate immune response to polymicrobial septic peritonitis by both MyD88-dependent and -independent processes and suggest that a major function of CCR2 in sepsis is to attenuate IL-10 production and IL-10-mediated suppression of host defense.

Acute Disease↗
PubMed2005

Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice.

The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. The lymphocytic (peri-)insulitis is preceded by an early accumulation of dendritic cells (DC) around the islets of Langerhans. This DC accumulation is thought to derive from an influx of monocytes attracted by pro-inflammatory chemokines. Besides chemokines, extracellular matrix (ECM) proteins play an important role in the accumulation of leukocytes in tissues. We studied the expression of the chemokines CCL2, CCL5, CXCL10, CCL19 and CCL21 over time in pancreases of NOD and control mice by ELISA on pancreas lysates as well as by immunohistochemistry. In addition, we studied the adhesive capacity of bone marrow-derived DC (BMDC) to ECM components. DC in the NOD pancreas accumulated at sites with an intense expression of fibronectin. In vitro, NOD BMDC showed increased fibronectin adhesion and increased VLA-5 expression. At the time of early DC accumulation (<10 wk), the lymphoid tissue-related chemokines CCL19 and CCL21 were increased. Our findings support the view that the early accumulation of DC around the NOD islets is not the consequence of an enhanced attraction of precursors and immature DC by pro-inflammatory chemokines. It rather might be the consequence of an aberrantly enhanced adhesion and retention of NOD DC.

Animals↗
PubMed2006

CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation.

Psoriasis is an immune-mediated skin disease characterized by lymphocytic infiltration and altered keratinocyte differentiation. Using immunohistochemical techniques we found that the cellular infiltrate in acute psoriatic plaques includes 5-8% CD3(-)CD56(+) natural killer (NK) cells, mostly localized in the mid and papillary dermis. NK lymphocytes isolated from punch biopsy specimens of psoriatic plaques showed a CD56(bright)CD16(-)CD158b(-) phenotype, failed to express the skin homing cutaneous lymphocyte-associated antigen and released abundant IFN-gamma upon stimulation. Supernatants from psoriatic NK cells induced MHC class II and ICAM-1 expression and release of CXCL10 and CCL5 by cultured psoriatic keratinocytes. Skin NK cells expressed high levels of the chemokines receptors CXCR3 and CCR5, intermediate amounts of CXCR1, CCR6 and CCR8, and low levels of CCR1, CCR2, CCR4, CCR7 and CX3CR1. In addition, they promptly migrated in vitro toward CXCL10, CCL5, supernatants of IFN-gamma-activated psoriatic keratinocytes and, to a lower extent, CCL20 and CCL4. In contrast, they failed to migrate toward CXCL8, CCL1, CCL2, CCL3, CCL17, CCL19 and CX3CL1. Taken together, our results implicate NK lymphocytes as newly identified protagonists in the pathogenesis of psoriasis. Their distinctive homing properties should be taken into account in the design of specific therapy aimed at blocking pathogenic cell accumulation in the skin.

CD56 Antigen↗
PubMed2006

Signaling events involved in cytokine and chemokine production induced by secretory phospholipase A2 in human lung macrophages.

Secretory phospholipases A(2) (sPLA(2)) are enzymes released during inflammatory reactions. These molecules activate immune cells by mechanisms either related or unrelated to their enzymatic activity. We examined the signaling events activated by group IA (GIA) and group IB (GIB) sPLA(2) in human lung macrophages leading to cytokine/chemokine production. sPLA(2) induced the production of cytokines (TNF-alpha, IL-6 and IL-10) and chemokines (CCL2, CCL3, CCL4 and CXCL8), whereas no effect was observed on IL-12, CCL1, CCL5 and CCL22. sPLA(2) induced the phosphorylation of the MAPK p38 and ERK1/2, and inhibition of these kinases by SB203580 and PD98059, respectively, reduced TNF-alpha and CXCL8 release. Suppression of sPLA(2) enzymatic activity by a site-directed inhibitor influenced neither cytokine/chemokine production nor activation of MAPK, whereas alteration of sPLA(2) secondary structure suppressed both responses. GIA activated the phosphatidylinositol 3-kinase (PI3 K)/Akt system and a specific inhibitor of PI3 K (LY294002) reduced sPLA(2)-induced release of TNF-alpha and CXCL8. GIA promoted phosphorylation and degradation of IkappaB and inhibition of NF-kappaB by MG-132 and 6-amino-4-phenoxyphenylethylamino-quinazoline suppressed the production of TNF-alpha and CXCL8. These results indicate that sPLA(2) induce the production of cytokines and chemokines in human macrophages by a non-enzymatic mechanism involving the PI3 K/Akt system, the MAPK p38 and ERK1/2 and NF-kappaB.

Cells, Cultured↗
PubMed2003

Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes.

Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immunoregulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified primary human fetal astrocyte cultures, we determined chemokine production using ELISA assays and RT-PCR and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNFalpha, IL-1beta, and IFNgamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2) and lesser amounts of RANTES (CCL5) and IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9), and fractalkine (CX(3)CL1) mRNA expression. Moreover, QUIN leads to upregulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human fetal astrocytes. Most of these effects were comparable to those induced by TNFalpha, IL-1beta, and IFNgamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation, particularly in ADC.

Astrocytes↗
PubMed2003

Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli.

Astrocytes play key roles in CNS development, inflammation, and repair by producing a wide variety of cytokines, chemokines, and growth factors. Understanding the regulation of this network is important for a full understanding of astrocyte functioning. In this study, expression levels of 268 genes encoding cytokines, chemokines, growth factors, and their receptors were established in cultured human adult astrocytes using cDNA arrays. Also, changes in this gene profile were determined following stimulation with TNFalpha, IL-1beta, and IFNgamma. The data obtained reveal a highly reproducible pattern of gene expression not only between different astrocyte cultures from a single source, but also between astrocytes from different donors. They also identify several gene products not previously described for human astrocytes, including a.o. IL-17, CD70, CD147, and BIGH3. When stimulated with TNFalpha astrocytes respond with increased expression of several genes, notably including those encoding the chemokines CCL2 (MCP-1), CCL5 (RANTES), and CXCL8 (IL-8), growth factors including BMP-2A, BMP-3, neuromodulin (GAP43), BDNF, and G-CSF, and receptors such as the CRF receptor, the calcitonin receptor (CTR), and TKT. The response to IL-1beta involves largely the same range of genes, but responses were blunted in comparison to the TNFalpha response. Treatment with IFNgamma had no or only marginal effects on expression of any of the 268 genes analyzed. Astrocytes treated with a mixture of all three stimuli together displayed responses that are largely similar to those found in response to TNFalpha or IL-1beta alone, with only few additional synergistic effects.

Aged↗
PubMed2004

Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells.

We have previously demonstrated that chloroquine may evoke inflammatory responses in the central nervous system by inducing expression of pro-inflammatory cytokines by astroglial cells. In this study, we further examined the molecular mechanism responsible for chloroquine-induced activation of NF-kappaB and subsequent expression of chemokines by astroglial cells. We observed that (1) chloroquine induced expression of chemokines such as CCL2 and CXCL8 in a dose- and time-dependent manner in human astroglial cells; (2) other lysosomotropic agents such as ammonium chloride and bafilomycin A1 had minimal effects on chemokine expression; (3) inhibition of NF-kappaB by MG-132 and TPCK suppressed chloroquine-induced mRNA expression of chemokines; (4) chloroquine increased the intracellular level of reactive oxygen species (ROS) in a dose- and time-dependent manner by human astroglial cells, but not by monocytic/microglial cells; (5) chloroquine-induced increase of intracellular ROS level was suppressed by pre-incubation with diphenyl iodonium (DPI) and N-acetyl cysteine (NAC); and (6) inhibition of chloroquine-induced ROS production by DPI or NAC suppressed chloroquine-mediated activation of NF-kappaB and subsequent mRNA expression of chemokines in astroglial cells. These results collectively suggest that chloroquine generates ROS, which is responsible for NF-kappaB activation and subsequent expression of pro-inflammatory chemokines in human astroglial cells.

Acetylcysteine↗
PubMed2005

Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes.

Activated glial cells have been implicated in the neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators have been proposed to play a role in glial cell-related brain damage; e.g., free radicals such as nitric oxide (NO), cytokines, and chemokines. Our laboratory has been interested in the effect of psychoactive drugs and their derivatives on the production of these mediators. Cannabinoids have been shown to possess immunomodulatory as well as psychoactive properties. We previously have shown that interleukin (IL)-1beta-stimulated human astrocytes, but not microglia, produce NO. In this study, we investigated the effects of the synthetic cannabinoid WIN55,212-2 on the production of several key inflammatory mediators by human fetal astrocytes activated by IL-1beta. Expression of the cannabinoid receptors CB1 and CB2 was detected on human astrocytes. WIN55,212-2 (10(-5) M) potently inhibited inducible NO synthase (iNOS) and corresponding NO production by IL-1beta-stimulated astrocytes. The CB1 and CB2 receptor-specific antagonists SR141716A and SR144528, respectively, partially blocked this suppressive effect. In addition, treatment of astrocytes with WIN55,212-2 downregulated in a concentration-dependent manner IL-1beta-induced tumor necrosis factor (TNF)-alpha release. Treatment with WIN55,212-2 also inhibited production of the chemokines CXCL10, CCL2 and CCL5 by IL-1beta-activated astrocytes. These findings indicate that WIN55,212-2 inhibits the production of inflammatory mediators by IL-1beta-stimulated human astrocytes and suggest that comparable agents may have therapeutic potential for the management of brain inflammation.

Astrocytes↗
PubMed2005

Differential activation of astrocytes by innate and adaptive immune stimuli.

The immunologic privilege of the central nervous system (CNS) makes it crucial that CNS resident cells be capable of responding rapidly to infection. Astrocytes have been reported to express Toll-like receptors (TLRs), hallmark pattern recognition receptors of the innate immune system, and respond to their ligation with cytokine production. Astrocytes have also been reported to respond to cytokines of the adaptive immune system with the induction of antigen presentation functions. Here we have compared the ability of TLR stimuli and the adaptive immune cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) to induce a variety of immunologic functions of astrocytes. We show that innate signals LPS- and poly I:C lead to stronger upregulation of TLRs and production of the cytokines IL-6 and TNF-alpha as well as innate immune effector molecules IFN-alpha4, IFN-beta, and iNOS compared with cytokine-stimulated astrocytes. Both innate stimulation and adaptive stimulation induce similar expression of the chemokines CCL2, CCL3, and CCL5, as well as similar enhancement of adhesion molecule ICAM-1 and VCAM-1 expression by astrocytes. Stimulation with adaptive immune cytokines, however, was unique in its ability to induce upregulation of MHC II and the functional ability of astrocytes to activate CD4(+) T cells. These results indicate potentially important and changing roles for astrocytes during the progression of CNS infection.

Adaptation, Biological↗
PubMed2005

Genetic expression profile of olfactory ensheathing cells is distinct from that of Schwann cells and astrocytes.

Olfactory ensheathing cells (OECs) accompany the axons of olfactory receptor neurons, which regenerate throughout life, from the olfactory mucosa into the olfactory bulb. OECs have shown widely varying efficacy in repairing the injured nervous system. Analysis of the transcriptome of OECs will help in understanding their biology and will provide tools for investigating the mechanisms of their efficacy and interactions with host tissues in lesion models. In this study, we compared the transcriptional profile of cultured OECs with that of Schwann cells (SCs) and astrocytes (ACs), two glial cell types to which OECs have similarities. Two biological replicates of RNA from cultured OECs, SCs, and ACs were hybridized to long oligo rat 5K arrays against a common reference pool of RNA (50% cultured fibroblast RNA and 50% neonatal rat brain RNA). Transcriptional profiles were analyzed by hierarchical clustering, Principal Components Analysis, and the Venn diagram. The three glial cell types had similarly increased or decreased expression of numerous transcripts compared with the reference. However, OECs were distinguishable from both SCs and ACs by a modest number of transcripts, which were significantly enriched or depleted. Furthermore, OECs and SCs were more closely related to each other than to ACs. Expression of selected transcripts not previously characterized in OECs, such as Lyz, Timp2, Gro1 (Cxcl1), Ccl2 (MCP1), Ctgf, and Cebpb, was validated by real-time reverse transcription-polymerase chain reaction (RT-PCR); immunohistochemistry in cultured OECs, SCs, and ACs, and adult tissues was performed to demonstrate their expression at the protein level.

Animals↗