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PubMed1985

Delayed type hypersensitivity to gangliosides in the Lewis rat.

Systematic study of the immunologic properties of gangliosides has been hampered by the lack of a suitable assay. In this study, significant delayed type hypersensitivity reactions to gangliosides were observed in Lewis rats immunized with whole guinea pig spinal cord (GP-SC) in complete Freund's adjuvant (CFA). The reaction was manifested by an increase in ear thickness after intradermal injection of a mixture of gangliosides and methylated bovine serum albumin (mBSA). No responses were observed to either gangliosides or mBSA alone. The reaction to gangliosides increased after immunization, persisted for 48 h, and was characterized by perivascular infiltration of mononuclear cells. Further evidence for a cellular response was demonstrated by the transfer of ganglioside-specific ear swelling by cultured spleen cells. The response to gangliosides was not due to contamination with myelin basic protein (BP) since no reaction to gangliosides was observed in GP-BP/CFA-immunized rats, and no reaction to BP was observed in ganglioside/CFA-immunized rats. In BP-immunized rats, responsiveness to BP persisted after recovery from clinical EAE for at least 60 days. However, no response to gangliosides was observed in BP-immunized animals after recovery from clinical EAE, suggesting the lack of autosensitization to gangliosides due to the disease process itself.

Animals↗
PubMed1999

Enhancement of the immune response to poorly immunogenic gangliosides after incorporation into very small size proteoliposomes (VSSP).

Certain gangliosides are tumor-associated antigens that constitute potential targets for cancer immunotherapy. A major drawback in the design of ganglioside-based cancer vaccines, however, is the poor immunogenicity of these glycolipids. Here we report the immunological and physicochemical properties of very small size proteoliposomes (VSSP) obtained by using anionic detergents to incorporate gangliosides into the outer membrane protein complex (OMPC) of N. meningitidis. VSSP of three different gangliosides, GM3, NGcGM3 and GD3, were tested. These gangliosides differ in level of expression in normal tissues and in immunogenicity in different animal species. We show that the immunization with VSSP in an oil adjuvant consistently induced both IgM and IgG anti-ganglioside antibodies. In the mouse, the anti-ganglioside IgG fraction was not restricted to the typical T-independent isotype IgG3. Unexpectedly, significant levels of the T-dependent IgG1, IgG2a and particularly IgG2b were also found. VSSP-mediated enhancement of the immunogenicity was not restricted to the relatively immunogenic ganglioside GD3, satisfactory immune responses against highly tolerated GM3 and NGcGM3 were also obtained. Similar results were achieved in chickens and monkeys. No reactogenicity was observed even when self-gangliosides were used for immunization. VSSP overcame natural tolerance to gangliosides in an adjuvant dependent fashion.

Adjuvants, Immunologic↗
PubMedDate not supplied

Role of tumor-associated gangliosides in cancer progression.

Neuroectodermic tumors can mostly be characterized by the presence of tumor-associated glycosphingolipid antigens, such as gangliosides, defined by monoclonal antibodies. Recently, cumulative evidence indicates that gangliosides modify the biological effects of several trophic factors, in vitro and in vivo, as well as the mitogenic signaling cascade that these factors generate. The functional roles of gangliosides in tumor progression can be revisited: (i) ganglioside antigens on the cell surface, or shed from the cells, act as immunosuppressors, as typically observed for the suppression of cytotoxic T cells and dendritic cells, (ii) certain gangliosides, such as GD3 or GM2, promote tumor-associated angiogenesis, (iii) gangliosides strongly regulate cell adhesion/motility and thus initiate tumor metastasis, (iv) ganglioside antigens are directly connected with transducer molecules in microdomains to initiate adhesion coupled with signaling, and (v) ganglioside antigens and their catabolites are modulators of signal transduction through interaction with tyrosine kinases associated with growth factor receptors or other protein kinases. Given the potential importance of these sialylated gangliosides and their modulating biological behavior in vivo, further studies on the role of gangliosides are warranted.

Adjuvants, Immunologic↗
PubMed2002

A novel heptasialosyl c-series ganglioside in embryonic chicken brain: its structure and stage-specific expression.

A ganglioside of unknown structure (ganglioside X) was purified from chicken brain at embryonic day 12 (E12) and characterized for its structure. Ganglioside X was reactive with a monoclonal antibody A2B5 and migrated below GH1c on thin-layer chromatography (TLC). Extensive treatment of ganglioside X with Clostridium perfringens sialidase produced a single ganglioside product. This ganglioside was identified as GM1 based upon its chromatographic mobility and reactivity to cholera toxin B subunit and anti-GM1 antibody. Partial hydrolysis of ganglioside X by sialidase generated several degradation products including GH1c, GP1c, and GQ1c. Electrospray ionization (ESI)-mass spectrometry (MS) of the permethylated derivative of ganglioside X produced a triple-charged parent ion peak at m/z 1355, which corresponded with the gangliotetraose oligosaccharide structure having seven sialic acids and ceramide with the molecular mass of 566 (as non-methylated form). Collision-induced dissociation (CID)-MS(2) showed fragment ions including those at m/z 1066 and 1931; these two ions matched the structures of (NeuAc)(3)-Gal-Glc-Cer and (NeuAc)(4)-Gal-GalNAc, respectively. These structures were confirmed by CID-MS(3) of the corresponding peaks. Based upon these findings, the structure of ganglioside X was identified as NeuAc-NeuAc-NeuAc-NeuAc-Galbeta1-3GalNAcbeta1-4(NeuAc-NeuAc-NeuAcalpha2-3)Galbeta1-4Glcbeta1-1'Cer. This ganglioside was designated as GS1c. A developmental study demonstrated that GS1c was expressed in chicken brain during a period from E6 to E13 and thereafter decreased rapidly in its concentration. The present study suggests that GS1c may play a specific role in early development of chicken brain.

Animals↗
PubMed2001

Liver gangliosides of various animals ranging from fish to mammalian species.

Liver gangliosides of different animal species were analyzed. Bony fish liver contained a major ganglioside that migrated faster than GM3 on thin-layer chromatography (TLC). This ganglioside was identified to be GM4 (NeuAc) by methods including product analysis after sialidase treatment and negative-ion electrospray ionization (ESI)-mass spectrometry (MS). The presence of GM4 (NeuGc) in fish liver was also demonstrated. The main ganglioside band of bovine liver consisted of two different molecular species, i.e. GD1a (NeuAc/NeuAc) and GD1a (NeuAc/NeuGc). Major gangliosides of liver tissue exhibited a distinct phylogenetic profile; GM4 was expressed mainly in lower animals such as bony fish and frog liver, whereas mammalian liver showed ganglioside patterns with smaller proportions of monosialo ganglioside species. While c-series gangliosides were consistently expressed in lower animals, they were found only in mammalian liver of particular species. No apparent trend was observed between the concentration of liver gangliosides and the phylogenetic stage of animals. The present study demonstrates the species-specific expression of liver gangliosides.

Animals↗
PubMed2001

Major and c-series gangliosides in lenticular tissues: mammals to molluscs.

Gangliosides of eye lenses were examined in mammals (rat, rabbits, pig, cow), bird (chicken), reptile (terrapin), amphibian (bullfrog), bony fish (red sea bream, bluefin tuna, bonito, Pacific mackerel) and molluscs (common squid, Pacific octopus). Besides the fact that GM3 was the common ganglioside species, the composition of major gangliosides in mammalian eye lenses significantly differed from each other. While gangliotetraose gangliosides were abundant in rat eye lens, they did not constitute major components in porcine and bovine tissues. The c-series ganglioside GT3 was expressed in rat eye lenses but were practically absent in other mammalian tissues. The composition of major gangliosides in eye lenses of lower animals varied from species to species, whereas c-series gangliosides were consistently expressed, showing similar compositional profiles. Our results demonstrate the species-specific compositions of lenticular gangliosides. Evidence was also provided suggesting that eye lenses of common squid (Todarodes pacificus) and Pacific octopus (Octopus vulgaris) express gangliosides including gangliotetraose species and c-series gangliosides.

Animals↗
PubMed1997

An immunohistochemical technique with a series of monoclonal antibodies to gangliosides: their differential distribution in the rat cerebellum.

Gangliosides, sialic acid-containing glycosphingolipids, are normal membrane constituents and are highly expressed in the vertebral central nervous system. Owing to their topological localization on the outer surface of neural plasma membranes and their unique chemical structure, gangliosides have been implicated in a variety of phenomena. It was, however, difficult to study the localization of gangliosides in the central nervous system because of the lack of useful probes for gangliosides. We recently established an improved method for the generation of mouse MAbs to gangliosides by immunizing C3H/HeN mice with purified gangliosides. Using this method, we succeeded in generating a large number of the MAbs specific for gangliosides. These MAbs enabled us to determine the localization of gangliosides in the rat brain. We previously described the differential distribution patterns of gangliosides in the brain regions by an immunohistochemical technique with MAbs. In the present paper, we describe an immunofluorescence technique for the detection of ganglioside distribution in the postnatal rat cerebellar cortex in detail. The principles of immunohistochemistry have been described in several review articles.

Animals↗
PubMed1982

Translocation of newly synthesized gangliosides to the cell surface.

A new method was developed to follow the translocation of gangliosides from their site of synthesis within the cell to the plasma membrane. Cultured mouse neuroblastoma N18 and rat glioma C6 cells were labeled for increasing times with D- [1-3H]galactose and then subjected to mild oxidation with NaIO4. Under the conditions chosen, oxidation was essentially restricted to cell-surface sialic acid residues, which were converted to derivatives with an aldehyde function. The labeled gangliosides were isolated from the cells and reacted with dinitrophenylhydrazine to form dinitrophenyl (DNP) derivatives of the oxidized gangliosides. The DNP-gangliosides then were separated from their unmodified counterparts by thin-layer chromatography. Thus, the rate of labeling of surface gangliosides was distinguished from the rate of labeling of total gangliosides. Our results indicated that the transfer of gangliosides from the site of synthesis to the cell surface required approximately 20 min and that newly synthesized gangliosides appeared to be transported to the plasma membrane at a constant rate. No essential differences were found in the rates of translocation of different ganglioside species by N18 cells or between gangliosides of N18 and C6 cells.

Animals↗
PubMed1986

Thermotropic characterization of phosphatidylcholine vesicles containing ganglioside GM1 with homogeneous ceramide chain length.

The thermotropic behavior of dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine large unilamellar vesicles containing ganglioside GM1 of homogeneous long chain base composition has been studied by high-sensitivity differential scanning calorimetry and fluorescence spectroscopy. At neutral pH and in the absence of Ca2+, the thermotropic behavior of these systems is independent of the ganglioside chain length composition. The presence of Ca2+ at concentrations higher than 5 mM induces ganglioside phase separation in a manner dependent upon the length difference between the ganglioside long chain base and the phosphatidylcholine acyl chains. The analysis of the chain length dependence of the thermotropic behavior suggests that the driving force for ganglioside phase separation is not a Ca2+-induced cross-bridging of the ganglioside head group but a passive ganglioside exclusion from Ca2+-perturbed phosphatidylcholine-rich regions within the bilayer. Experiments with native ganglioside GM1, primarily a mixture of C18:1 and C20:1 long chain bases, indicate that the individual components of the mixture maintain their characteristic behavior within the lipid bilayer matrix. These results, together with the presence of a phase transition in native GM1 micellar dispersions, absent in purified C18:1 or C20:1 ganglioside micelles, strengthen the idea of a possible role of chain length composition in the modulation of ganglioside function.

Animals↗
PubMed2003

Gangliosides regulate tumor cell adhesion to collagen.

The ability of tumor cells to adhere to extracellular matrix proteins is critical for migration and invasion. The factors that regulate tumor cell adhesion are poorly characterized. Gangliosides promote platelet adhesion and may also play a role in the adhesion of other cell types. We hypothesized that pharmacological depletion of membrane gangliosides from adherent cells would abrogate adhesion to collagen and promote migration and invasion. To test these hypotheses, LA-N1 neuroblastoma cells, which avidly adhere to collagen and are rich with membrane gangliosides (43.69 nmol/10(8) cells), were cultured in the presence of D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol-HCl. Endogenous gangliosides were reduced by 98% (0.76 nmol/10(8) cells) and adhesion to collagen decreased by 67%. There were no changes in cell morphology, viability, proliferation rate or apoptosis. Pre-incubation of ganglioside-depleted cells in conditioned medium from control cells restored adhesion to collagen (0.45 +/- 0.002), comparable to that of control cells (0.49 +/- 0.035). Similarly, pre-incubation of ganglioside-depleted cells with purified GD2 completely restored adhesion in a concentration-dependent manner. When LA-N1 cells were cultured with retinoic acid, a biological response modifier known to increase endogenous gangliosides, adhesion to collagen increased. Next, we questioned whether changes in adhesion would be reflected as changes in migration and invasion. Cells depleted of endogenous cellular gangliosides migrated more than control cells. Finally, control cells replete with their endogenous gangliosides demonstrated less invasive potential than control cells. The data demonstrate that endogenous tumor gangliosides increase neuroblastoma cell adhesion to collagen and reduce migration and invasion in vitro.

Animals↗
PubMed1994

Nephron segment and cell-type specific expression of gangliosides in the developing and adult kidney.

Despite the increasing knowledge of the role of gangliosides in normal and diseased tissues, little is known of the presence, distribution and functions of these molecules in the kidney. In this study we analyzed the main gangliosides of isolated glomeruli and cortical, medullary and papillary fractions of the human, rat and bovine kidneys biochemically. In addition, we used immunohistochemistry to visualize the distribution of GM1/GM2, GD2, GD3 and O-acetyl GD3 gangliosides along the nephron. Furthermore, we explored the species specific expression of gangliosides by comparing those from the rat, bovine and human kidney, and studied the pattern of ganglioside expression during development. In glomeruli, cortical tubuli, medullae and papillae, a relatively simple pattern of main gangliosides was observed as revealed by thin layer chromatographic (TLC) analysis in each species studied. Furthermore, considerable changes in the glomerular gangliosides during maturation were observed, with a complex type of gangliosides predominating during the fetal age and with a preference to more simple precursors upon maturation. Interestingly, the immunohistochemical detection revealed a distinct pattern of ganglioside compartmentation to various nephron segments or cell types. These findings provide a basis for studying the role of segment- and cell type-specific gangliosides for local functions.

Aging↗
PubMed1982

Kinetics of Vibrio cholerae sialidase action on gangliosidic substrates at different supramolecular-organizational levels.

G(d1a), G(d1b) and G(t1b) gangliosides were dispersed in the following membrane-mimicking systems: (a) homogeneous micelles; (b) mixed micelles with G(m1) ganglioside (which is resistant to the enzyme action), Triton X-100 or bovine serum albumin; (c) small unilamellar vesicles of egg phosphatidylcholine. The effect of dispersion on sialic acid release by Vibrio cholerae sialidase was studied. As reference substrates freely interacting with the enzyme the lipid-free carbohydrates of G(d1a) and 3'-sialosyl-lactose were employed. The apparent V(max.) of the enzyme was, with all the gangliosides, dependent on the type of ganglioside dispersion. It was lowest for homogeneous micelles and mixed micelles with ganglioside G(m1), and increased about 6-fold for ganglioside/bovine serum albumin lipoprotein micelles, 15-fold for mixed-ganglioside/Triton X-100 micelles (optimal molar ratio 1:7.5) and 30-fold for phosphatidylcholine vesicles containing 2.5 mol% ganglioside (this proportion was optimal for enzyme activity on the vesicles). For ganglioside G(d1a), the activity on Triton X-100 mixed micelles and on mixed vesicles was even greater (3- and 6-fold respectively) than that displayed on G(d1a) lipid-free carbohydrate. With each of the used gangliosides the apparent K(m) values were very similar values for homogeneous micelles and vesicular dispersions, but showed marked increases for Triton X-100 mixed micelles, approaching the values exhibited by reference oligosaccharides. Triton X-100 micelles and phosphatidylcholine vesicles did not appreciably alter the kinetics of sialidase action on 3'-sialosyl-lactose and on G(d1a) lipid-free carbohydrate, indicating that the above effects are dependent on the intrinsic characteristics of the membrane-like systems containing gangliosides.

Cell Membrane↗
PubMed1995

n-Butyrate mediation of ganglioside expression of human and murine cancer cells demonstrates relative cell specificity.

1. n-Butyrate, a short chain fatty acid produced by colonic fermentation, induces differentiation in human neoplastic cell lines, and reduces expression in vitro of a sialyltransferase that glycosylates N-linked glycoproteins in hepatoblastoma cells. Gangliosides are amphipathic, sialylated glycosphingolipids that undergo profound changes in many transformed cells and may protect neoplastic cells from host immune surveillance. Colonic mucosal cells are exposed to luminal short-chain fatty acid concentrations of up to 80 mmol/l, and there is some evidence that short-chain fatty acids may alter ganglioside expression in colon cancer cells. 2. Because of the importance of gangliosides in cancer pathogenesis, we investigated the effects of n-butyrate on ganglioside expression of colonic (human and murine) and non-colonic cancer cells. 3. Three separate colon cancer cell lines (LS174T, T84 and MCA-38), when butyrate treated, demonstrated striking amplification of specific individual gangliosides. However, the total lipid-bound sialic acid content of gangliosides of butyrate-treated LS174T cells diminished. In contrast to earlier reports, n-butyrate did not mediate expression of all gangliosides and specifically did not mediate expression of GM3. This effect persisted even after removal of butyrate. 4. In contrast, exposure of extracolonic cells to butyrate, including cervical cancer (HeLa) and laryngeal cancer (HEp-2) cell lines in this study and hepatoblastoma cells (Hep G2) in our previous work, caused no detectable changes in ganglioside expression. 5. In conclusion, our results indicate a relative tissue specificity of butyrate-mediated alterations in ganglioside expression that is not universal but is limited to specific gangliosides.

Animals↗
PubMed2002

Ganglioside loss promotes survival primarily by activating integrin-linked kinase/Akt without phosphoinositide 3-OH kinase signaling.

Keratinocyte gangliosides influence cellular functions, including proliferation, adhesion, migration, and differentiation. The effects of endogenous depletion of membrane gangliosides by gene transfection of a human ganglioside-specific sialidase on cell survival were investigated. Ganglioside depletion promotes survival of the human keratinocyte-derived SCC12 cell line through upregulated phosphorylation of beta1 integrin, and increased phosphorylation and activity of integrin-linked kinase, protein kinase B/Akt, and Bad, with resultant inhibition of caspase-9 activation. Ganglioside deficiency also increases expression of cyclins D1 and E, promoting cell cycle progression from G1 phase to S phase. Inhibition of either protein kinase B/Akt or integrin-linked kinase activity renders the ganglioside-deficient cells susceptible to triggers of apoptosis. Both serine-473 and threonine-308 sites of protein kinase B/Akt show increased phosphorylation in ganglioside-deficient cells, but the cell survival correlates with increased phosphorylation of the serine-473 site of Akt, not with increased phosphorylation of the threonine-308 site. Consistently, blockade of ganglioside GT1b function activates integrin-linked kinase and only the serine-473 site of protein kinase B/Akt. In contrast, antibody-induced blockade of GM3 function increases only threonine-308 phosphorylation of ganglioside-deficient cells. Whereas blockade of phosphoinositide 3-OH kinase function suppresses threonine-308 phosphorylation, it neither inhibits serine-473 phosphorylation nor triggers apoptosis. These data suggest that ganglioside depletion modulates cell survival primarily through protein kinase B/Akt stimulation by a pathway that does not require phosphoinositide 3-OH kinase and epidermal growth factor receptor signaling.

Apoptosis↗
PubMed2001

Human platelets express gangliosides with LKE activity and ABH blood group activity.

BACKGROUND: Platelets express several neutral glycosphingolipids with ABH and P blood group activity that may play a role in infectious, autoimmune, and alloimmune thrombocytopenia. In RBCs, sialylated glycosphingolipids or gangliosides with blood group activity have also been reported. To determine whether similar antigens are expressed by platelets, the total platelet ganglioside fraction was isolated and screened for blood-group-active glycosphingolipids. STUDY DESIGN AND METHODS: Platelet gangliosides were isolated by organic extraction, base hydrolysis, anion exchange, silicic acid, and high-performance liquid chromatography. Gangliosides were identified and characterized by high-performance thin-layer chromatography-immunostaining with blood group-specific MoAbs and glycosidase digestion. RESULTS: Group A, but not group O, platelets express five gangliosides with group A activity. Of five A MoAbs and lectins examined, only MoAbs Birma-1 and MHO4 recognized all five sialyl A bands. The sialyl A bands were sensitive to endoglycoceramidase and neuraminidase. One sialyl A band may represent a branched ganglioside with sialyl-I and group A activity. Platelets also express an LKE-active ganglioside consistent with sialyl-galactosylgloboside. CONCLUSION: In addition to sialyl-iI and sialyl-Le(x) gangliosides, group A platelets express gangliosides with LKE activity and group A activity. Like RBCs, group A-active gangliosides may act as alloantigens and autoantigens to naturally occurring isohemagglutinins.

ABO Blood-Group System↗
PubMed1976

Thyrotropin-ganglioside interactions and their relationship to the structure and function of thyrotropin receptors.

Gangliosides inhibit 125I-labeled thyrotropin binding to the thyrotropin receptors on bovine thyroid plasma membranes, on guinea pig retro-orbital tissue plasma membranes, and on human adipocyte membranes. This inhibition by gangliosides is critically altered by the number and location of the sialic acid residues within the ganglioside structure, the efficacy of inhibition having the following order: GD1b greater than GT1 greater than GM1 greater than GM2 = GM3 greater than GD1a. The inhibition results from the interaction of thyrotropin and gangliosides, rather than the interaction of membrane and gangliosides. Fluorescence studies show that the inhibition is associated with a distinct conformational change of the thyrotropin molecule and that the progression from a "noninhibitory conformation" to an "inhibitory conformation" parallels exactly the order of effectiveness in inhibiting 125I-labeled thyrotropin binding. The ganglioside inhibition of 125I-labeled thyrotropin binding appears to be hormonally specific in that it is not affected by albumin, glucagon, insulin, prolactin, follicle-stimulating hormone, growth hormone, or corticotropin. The possibility that a ganglioside or ganglioside-like structure is a component of the thyrotropin receptor is suggested by the finding that gangliosides more complex than N-acetylneuraminylgalactosylglucosylceramide are present in bovine thyroid membranes in much higher quantities than have been previously found in extraneural tissue. The finding that the B component of cholera toxin, which also interacts with gangliosides, has a peptide sequence in common with the beta subunit of thyrotropin, suggests that thyrotropin and cholera toxin may be analogous in their mode of action on the membrane.

Adipose Tissue↗
PubMed1996

Ganglioside synthesis during the development of neuronal polarity. Major changes occur during axonogenesis and axon elongation, but not during dendrite growth or synaptogenesis.

Changes in the levels and types of gangliosides occur during neuronal differentiation and development, but no studies have correlated these changes with defined events in neuronal morphogenesis. Here, we have analyzed the relationship between ganglioside synthesis and the development of axons and dendrites in polarized neurons, using hippocampal neurons cultured in such a way that axons and dendrites are generated by a defined sequence of events and in which there is virtually no contamination by glial cells. Neurons were labeled with [4,5-3H]dihydrosphingosine, which was rapidly incorporated into cells and metabolized to 3H-labeled glycosphingolipids. The rate of 3H-labeled glycosphingolipid synthesis was directly proportional to the initial rate of [4,5-3H]dihydrosphingosine uptake and was linear versus time for up to 9 h of incubation. The major changes in 3H-labeled ganglioside synthesis occurred during the period of axonogenesis and rapid axon growth. During axonogenesis, there was a significant increase in the synthesis of complex gangliosides (i.e. GM1, GD1a, GD1b, and GT1b) with a corresponding reduction in the synthesis of glucosylceramide and ganglioside GD3. During the stage of rapid axon growth, the ratio of a- to b-series gangliosides increased significantly. However, during dendritogenesis, dendrite growth, and synaptogenesis, there was little change in ganglioside synthesis, with a small and gradual increase in the ratio of a- to b-series gangliosides and an increase in the synthesis of gangliosides GD1a and GT1b. These results indicate that despite major changes in neuronal morphology and functionality as neurons mature, changes in ganglioside synthesis are restricted to early stages of neuronal development, namely axonogenesis and rapid axon elongation.

Animals↗
PubMed2002

JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells.

Neuronal cell membranes are particularly rich in gangliosides, which play important roles in brain physiology and pathology. Previously, we reported that gangliosides could act as microglial activators and are thus likely to participate in many neuronal diseases. In the present study we provide evidence that JAK-STAT inflammatory signaling mediates gangliosides-stimulated microglial activation. Both in rat primary microglia and murine BV2 microglial cells, gangliosides stimulated nuclear factor binding to GAS/ISRE elements, which are known to be STAT-binding sites. Consistent with this, gangliosides rapidly activated JAK1 and JAK2 and induced phosphorylation of STAT1 and STAT3. In addition, gangliosides increased transcription of the inflammation-associated genes inducible nitric-oxide synthase, ICAM-1, and MCP-1, which are reported to contain STAT-binding elements in their promoter regions. AG490, a JAK inhibitor, reduced induction of these genes, nuclear factor binding activity, and activation of STAT1 and -3 in gangliosides-treated microglia. AG490 also inhibited gangliosides-induced release of nitric oxide, an inflammation hallmark. Furthermore, AG490 markedly reduced activation of ERK1/2 MAPK, indicating that ERKs act downstream of JAK-STAT signaling during microglial activation. However, AG490 did not affect activation of p38 MAPK. We also report that the sialic acid residues present on gangliosides may be one of the essential components in activation of JAK-STAT signaling. The present study indicates that JAK-STAT signaling is an early event in gangliosides-induced brain inflammatory responses.

Animals↗