Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of TNF-alpha in the host defence mechanism against infection with a virulent strain of Cryptococcus neoformans. Administration of exogenous recombinant human TNF-alpha significantly prolonged the survival time of mice infected by intratracheal instillation of the organism. Surprisingly, neutralizing MoAb to murine TNF-alpha did not shorten their survival time, a finding inconsistent with previous results. To investigate the cause of this inconsistency, we examined the production of TNF-alpha in the lungs of infected mice. During the course of cryptococcosis, there was little or no generation of TNF-alpha mRNA in the lung. This might be partly due to a direct inhibitory action of the fungal microorganism of TNF-alpha production by macrophages. In vitro production of TNF-alpha by murine interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-stimulated macrophages was strongly inhibited by co-culturing with the whole yeast cells. In contrast, administration of recombinant murine IL-12 markedly induced TNF-alpha production and the neutralizing anti-TNF-alpha MoAb strongly blocked IL-12-induced protection of mice against cryptococcal infection. These results indicate that endogenously synthesized TNF-alpha has the potential to contribute to the elimination of C. neoformans and partly mediates the protective effect of IL-12.
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PMID:Contribution of tumour necrosis factor-alpha (TNF-alpha) in host defence mechanism against Cryptococcus neoformans. 897 14

The chemokine monocyte chemoattractant protein 1 (MCP-1) is produced predominantly by mononuclear phagocytes and stimulates recruitment into infected tissues of blood monocytes and T cells. These cell types are thought to be critical to host defenses against infections due to Cryptococcus neoformans, a major cause of disease in persons with AIDS and other disorders of cell-mediated immunity. Accordingly, in the present study, we examined the conditions under which human monocytes and bronchoalveolar macrophages (BAM) are stimulated by C. neoformans to produce MCP-1. C. neoformans was a potent inducer of MCP-1 release from monocytes, with levels of chemokine secreted similar to that seen following stimulation with lipopolysaccharide (LPS). BAM, in contrast, were stimulated by LPS, but not by C. neoformans, to secrete MCP-1. A peak in MCP-1 mRNA was seen 8 h following cryptococcal stimulation of monocytes. Nine strains of C. neoformans stimulated monocytes to release MCP-1, and there was only modest variation between strains. However, when an individual strain was used, the capacity of C. neoformans to stimulate monocyte MCP-1 release did vary, depending upon the conditions used to grow the fungal stimuli. Finally, C. neoformans stimulated comparable quantities of MCP-1 release in monocytes from donors with and without human immunodeficiency virus infection. These data establish C. neoformans as a potent stimulator of MCP-1 in monocytes, but not in BAM. The failure of C. neoformans to stimulate MCP-1 in BAM, if occurring in vivo, could result in a diminished cell-mediated inflammatory response following inhalation of airborne fungi.
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PMID:Variables affecting production of monocyte chemotactic factor 1 from human leukocytes stimulated with Cryptococcus neoformans. 903 95

We examined the effect of Cryptococcus neoformans on nitric oxide (NO) production by activated cultured macrophages. C. neoformans suppressed NO production by murine peritoneal macrophages stimulated with bacterial lipopolysaccharide (LPS) and interferon (IFN)-gamma, while it did not influence the production of IL-1 beta. This effect was observed when 1 x 10(6) or 10(7) of C. neoformans was added to macrophage cultures. A direct contact of C. neoformans with macrophages was essential for this inhibitory effect, since placement of a 0.45-micron-pore membrane between the organism and macrophages prevented such effect. In addition, C. neoformans killed by heat or paraformaldehyde did not show this inhibitory activity. Capsular polysaccharide did not mediate the inhibitory effect, since two nonencapsulated mutant strains of C. neoformans showed an inhibitory activity similar to that of encapsulated wild strains, and culture supernatants of C. neoformans, rich in polysaccharide antigens, did not inhibit macrophage NO production compared with control culture medium. The inhibitory effect was also not mediated by interleukin (IL)-10 and transforming growth factor (TGF)-beta since neutralizing specific antibodies to these cytokines did not influence C. neoformans-induced reductions in macrophage NO production. Our results suggest that C. neoformans may cause a direct suppression of NO-mediated fungicidal activity of macrophages, and the effect is independent of the capsular polysaccharide and production of IL-10 and TGF-beta.
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PMID:Cryptococcus neoformans inhibits nitric oxide production by murine peritoneal macrophages stimulated with interferon-gamma and lipopolysaccharide. 931 38

In this study, we demonstrated the anti-chemotactic activity of the capsular polysaccharides (CPSs) isolated from each of the heavily (H)- and weakly (W)-encapsulated strains of Cryptococcus neoformans in vitro. The capacity for activation of the alternative complement pathway (ACP) of cells of the two C. neoformans strains in fresh human sera was comparable to that of zymosan (insoluble control), whereas the capacity for generation of the chemotactic factor (CF) of the cells of the two strains in fresh murine sera was markedly lower in the order H- < W-strain than that of zymosan. Conversely, the capacities for ACP activation and CF generation of the CPSs were extremely lower than those of lipopolysaccharide (LPS, soluble control). When zymosan-activated murine serum was incubated with CPS, both CPSs inhibited CF activity dose dependently. When zymosan-activated serum was incubated with heat-killed cells of each strain of C. neoformans, H and W, the CF activity of the treated sera decreased significantly, suggesting that CPS per se did not affect the neutrophils directly, but CPS absorbed CF. On the other hand, both CPSs were shown to possess the O-acetyl groups in their molecules by 1H-nuclear magnetic resonance spectroscopy. The de-O-acetylation of both CPSs increased the capacity for ACP activation to a level similar to that of LPS, and the de-O-acetylated CPS of both strains exhibited a lower ability to inhibit CF than did native CPS. Collectively, these results suggest that the anti-chemotactic activity of CPS accounts for its ability to absorb the CF which was mostly generated at the sites around the cell wall of whole cells via the ACP, thus suppressing the inflammatory response by preventing dispersal of CF to the extracellular space; and also that the O-acetyl group is partly, if any, involved in the mechanism for incompetence in ACP activation as well as the inhibition of CF.
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PMID:Anti-chemotactic activity of capsular polysaccharide of Cryptococcus neoformans in vitro. 934 15

Lewis rat alveolar macrophages (AM) were harvested and exposed in vitro to Cryptococcus neoformans to investigate the induction of inflammatory cytokines. AM in tissue culture wells were incubated with viable yeast cells of C. neoformans or the capsular polysaccharide, glucuronoxylomannan (GXM), with or without rabbit anti-C. neoformans antiserum. At 3, 6, 12 and 24 h, AM were washed, lyzed and total RNA was isolated. Using reverse transcription-PCR, the transcripts of cytokine genes were semi-quantified by comparison with constitutive transcripts. Incubation of AM with lipopolysaccharide, as positive control, induced elevated levels of the three transcripts measured: interleukin (IL)-1 alpha, IL-6 and tumour necrosis factor (TNF)-alpha. Under the same conditions, no obvious changes were observed in the levels of transcription of these cytokines by AM after exposure to several strains of C. neoformans. However, AM that were incubated with both the yeast cells and rabbit polyclonal antisera to C. neoformans manifested significantly increased levels of mRNA for IL-6, but not IL-1 alpha or TNF-alpha. This increased level of IL-6 mRNA was detectable after incubation for 6 or 12 h. Levels of transcription in AM were unaffected by exposure to normal rabbit serum, specific antiserum alone. GXM at concentrations of 10, 100 or 500 micrograms ml-1, or GXM and antiserum. Adsorption of the antiserum with heat-killed yeast cells of C. neoformans diminished its ability to induce IL-6 mRNA in combination with fresh, viable yeast cells. The induction of IL-6 mRNA by yeast cells and antiserum does not require intact complement. In the absence of complement, the rabbit antiserum served as a potent opsonin and markedly increased phagocytosis of C. neoformans by AM. These results indicate that antibody-opsonized C. neoformans are readily phagocytosed by rat AM, and that antibody-mediated phagocytosis may differ from complement-mediated phagocytosis in the subsequent stimulation of IL-6.
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PMID:Induction of interleukin-6 mRNA in rat alveolar macrophages by in vitro exposure to both Cryptococcus neoformans and anti-C. neoformans antiserum. 940 25

Using two isogenic strains of Cryptococcus neoformans, we studied the influence of the capsule in C. neoformans microglial-cell interaction. We demonstrate that the acapsular mutant yeasts (CAP67) are more susceptible to phagocytosis and killing than encapsulated yeasts (B3501) by the murine microglial cells, BV-2. RT-PCR analysis showed that the pattern of gene transcripts for tumour necrosis factor alpha (TNF-a), interleukin (IL)-1beta, IL-6, IL-12p40 and granulocyte macrophage colony stimulating factor remains unchanged following BV-2 cell infection with CAP67 or B3501 yeasts. Moreover, no induction of TNF-alpha secretion occurs in BV-2 cells infected with either B3501 or CAP67 yeasts or exposed to glucuronoxylomannan (GXM) or galactoxylomannan (GalXM). Nevertheless, lipopolysaccharide-induced TNF-alpha secretion is downregulated by cell infection with B3501 or CAP67 yeasts or exposure to GXM or GalXM. Overall, by means of a continuous cell line, it appears that the C. neoformans capsule is detrimental to microglial cell antifungal activity, while no effect can be attributed to the capsule as trend of cytokine gene expression and TNF-alpha secretion.
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PMID:Role of the capsule in microglial cell-Cryptococcus neoformans interaction: impairment of antifungal activity but not of secretory functions. 977 34

Inducible nitric oxide synthase (iNOS) is required in immune response against infections and is involved in granuloma formation in animals; in murine macrophages, iNOS is induced by lipopolysaccharide and interferon-gamma. In contrast, the role of iNOS in human immune response against infections is still questioned, and its expression in granulomas is poorly investigated. Using Western blotting and immunohistochemistry, we investigated iNOS expression in human lymph nodes with nonspecific reactions and in tissues containing granulomas caused by mycobacteria, Toxoplasma, Cryptococcus neoformans, Leishmania, Bartonella, noninfectious granulomas (sarcoidosis, foreign body), and other hystiocitic reactions (Kikuchi's disease, Omenn syndrome). iNOS was undetectable in nonspecific reactive lymphadenitis, foreign-body granulomas, and Omenn syndrome, whereas it was strongly expressed in infectious granulomas, sarcoidosis, and Kikuchi's diseases. Immunohistochemistry demonstrated that iNOS was selectively expressed by the epithelioid and multinucleated giant cells within the granulomas. Use of an anti-nitrotyrosine antibody, recognizing nitrosilated amino acid residues derived from nitric oxide production, revealed a consistent positivity within the cells expressing iNOS, thus suggesting that iNOS is functionally active. Detection of cytokines by reverse transcriptase-polymerase chain reaction demonstrated that tissues that were positive for iNOS, also expressed the Thl-type cytokine interferon-gamma mRNA, but not the Th2-type cytokine interleukin-4. Taken together, these results indicate that iNOS is involved in different human immune reactions characterized by histiocytic/granulomatous inflammation and associated with Th1-type cytokine secretion.
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PMID:Expression of inducible nitric oxide synthase in human granulomas and histiocytic reactions. 991 29

In the present study, we examined the in vitro effect of Cryptococcus neoformans on the production of interleukin-12 (IL-12) and IL-10 by murine macrophages. At a dose of 1 x 10(5), 1 x 10(6) or 1 x 10(7) ml-1, a highly virulent strain of C. neoformans (strain YC-11) suppressed the production of IL-12p40 by a murine macrophage cell line, J774.1 stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma, while the production of IL-10 was not inhibited, but rather slightly augmented. The suppression of IL-12p40 production did not change by neutralizing anti-IL-10 mAb. A direct contact of C. neoformans with macrophages was largely involved in this inhibitory effect, since placement of a 0.45 micron pore membrane between the organism and macrophages prevented such effect. On the other hand, the culture supernatant of YC-11 did not inhibit macrophage IL-12p40 production when used at a lower dose, which contained an equivalent amount of capsular polysaccharide to that in the supernatant of YC-11 cultured at 1 x 10(5) or 1 x 10(6) ml-1, although it showed a small suppression at higher doses. Our results suggest that C. neoformans may suppress the induction of Th1 responses by inhibiting macrophage IL-12 production predominantly through a direct contact-dependent mechanism and to a lesser extent by a certain soluble factor(s) released from this microorganism.
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PMID:Differential effect of Cryptococcus neoformans on the production of IL-12p40 and IL-10 by murine macrophages stimulated with lipopolysaccharide and gamma interferon. 1036 12

It is generally believed that neutrophils from HIV-infected patients are functionally competent, but several studies have shown impairment in neutrophil fungal killing and cytokine production. In this study we evaluated the ability of neutrophils from healthy donors and HIV-infected patients to produce IL-12 in response to stimulation with Candida albicans, lipopolysaccharide (LPS) and Cryptococcus neoformans (acapsular and encapsulated), with and without MoAb opsonization. Neutrophils from healthy donors secreted IL-12 in response to LPS or C. albicans but not in response to encapsulated or acapsular C. neoformans, regardless of MoAb opsonization. Surprisingly, neutrophils from HIV-infected patients demonstrated constitutive IL-12 production, although these cells were not responsive to LPS stimulation. The inability of MoAb to C. neoformans capsular polysaccharide to promote IL-12 production by neutrophils excludes phagocytosis and/or CD16 cross-linking in this process, and distinguishes neutrophils from monocytes. Our results provide additional evidence for cytokine dysregulation in neutrophils from HIV-infected patients. Furthermore, the IL-12 response of neutrophils and monocytes to CD16 stimulation appears to be different, suggesting differences in the role of these phagocytic cells during the inflammatory response.
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PMID:Dysregulation in IL-12 secretion by neutrophils from HIV-infected patients. 1093 Nov 47

We characterized the expression of the beta-chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES by primary human microglia after exposure to Cryptococcus neoformans. In the absence of specific antibody, C. neoformans failed to elicit a chemokine response, while in the presence of specific antibody, microglia produced MIP-1alpha and MIP-1beta in amounts comparable to those induced by lipopolysaccharide. RANTES was also induced but at much lower levels. In addition to MIP-1alpha and MIP-1beta mRNA, we observed a robust induction of monocyte chemoattractant protein 1 and interleukin-8 mRNA following incubation of microglia with opsonized C. neoformans. In contrast, cryptococcal polysaccharide did not induce a chemokine response even when specific antibody was present and inhibited the MIP-1alpha induction associated with antibody-mediated phagocytosis of C. neoformans. The role of the Fc receptor in the observed chemokine induction was explored in several experiments. Treatment of microglia with cytochalasin D inhibited internalization of C. neoformans but did not affect MIP-1alpha induction. In contrast, treatment with herbimycin A, a tyrosine kinase inhibitor, inhibited MIP-1alpha induction. Microglia stimulated with immobilized murine immunoglobulin also produced MIP-1alpha and RANTES (MIP-1alpha > RANTES). Our results show that microglia produce several chemokines when stimulated by C. neoformans in the presence of specific antibody and that this process is likely to be mediated by Fc receptor activation. This response can be down-regulated by cryptococcal capsular polysaccharide. These findings suggest a mechanism by which C. neoformans infections fail to induce strong inflammatory responses in patients with cryptococcal meningoencephalitis and have important implications for antibody therapy.
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PMID:Cryptococcus neoformans induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta in human microglia: role of specific antibody and soluble capsular polysaccharide. 1117 58


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