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Biological activities of Bacteroides forsythus lipoproteins and their possible pathological roles in periodontal disease 总被引:2,自引:0,他引:2 下载免费PDF全文
Hasebe A Yoshimura A Into T Kataoka H Tanaka S Arakawa S Ishikura H Golenbock DT Sugaya T Tsuchida N Kawanami M Hara Y Shibata K 《Infection and immunity》2004,72(3):1318-1325
Bacteroides forsythus is a gram-negative, anaerobic, fusiform bacterium and is considered to be an etiological agent in periodontal disease. A lipoprotein fraction prepared from B. forsythus cells by Triton X-114 phase separation (BfLP) activated human gingival fibroblasts and a human monocytic cell line, THP-1, to induce interleukin-6 production and tumor necrosis factor alpha production. BfLP was found to be capable of inducing nuclear factor-kappaB translocation in human gingival fibroblasts and THP-1 cells. By using Chinese hamster ovary K1 cells transfected with Toll-like receptor genes together with a nuclear factor-kappaB-dependent CD25 reporter plasmid, it was found that signaling by BfLP was mediated by Toll-like receptor 2 but not by CD14 or Toll-like receptor 4. BfLP induced apoptotic cell death in human gingival fibroblasts, KB cells (an oral epithelial cell line), HL-60 cells (a human myeloid leukemia cell line), and THP-1 cells but not in MOLT4 cells (a T-cell leukemia cell line). Caspase-8, an initiator caspase in apoptosis, was found to be activated in these cells in response to BfLP stimulation. Thus, this study suggested that BfLP plays some etiological roles in oral infections, especially periodontal disease, by induction of cell activation or apoptosis. 相似文献
4.
Involvement of CD14 and beta2-integrins in activating cells with soluble and particulate lipopolysaccharides and mannuronic acid polymers 总被引:1,自引:0,他引:1 下载免费PDF全文
Flo TH Ryan L Kilaas L Skjâk-Braek G Ingalls RR Sundan A Golenbock DT Espevik T 《Infection and immunity》2000,68(12):6770-6776
Lipopolysaccharide (LPS) and related bacterial products can be recognized by host inflammatory cells in a particulate, bacterium-bound form, as well as in various soluble, released forms. In the present study we have compared the mechanisms used by LPS, detoxified LPS (DLPS), and mannuronic acid polymers (M-polymers), in solution or covalently linked to particles, in stimulating monocytes to tumor necrosis factor (TNF) production. The addition of recombinant LPS binding protein (LBP) and/or soluble CD14 (sCD14) enhanced the production of TNF from monocytes stimulated with soluble LPS, DLPS, or M-polymer, but did not affect the response to M-polymer or DLPS attached to particles. Treatment of monocytes with antibody to CD14, CD18, or CD11b showed that CD14, but not CR3 (CD11b/CD18), mediated monocyte TNF production in response to the soluble antigens. In contrast, anti-CD14, anti-CD11b and anti-CD18 monoclonal antibodies all inhibited the response to the particulate stimuli. On the other hand, B975, a synthetic analog of Rhodobacter capsulatus lipid A, completely abrogated the monocyte TNF response induced by LPS but did not affect the TNF induction by DLPS or M-polymer, either in soluble or particulate forms. These data demonstrate that the engagement of immune receptors by bacterial products such as LPS, DLPS, and M-polymer is dependent upon the presentation form of their constituent carbohydrates, and that factors such as aggregation state, acylation, carbohydrate chain length, and solid versus liquid phase of bacterial ligands influence the mechanisms used by cells in mediating proinflammatory responses. 相似文献
5.
乳腺管状小叶癌(Tubulolobular carcinoma,TLC)最初是被作为小叶癌的管状变型。作者总结了27例TLC的组织学、免疫表型和临床特征,并与纯小管癌和经典型小叶癌进行了比较。此组患者年龄43-79岁(中位年龄60岁)。1例双侧乳腺受累,5例病变为多灶性。肿瘤直径0.5-2.5cm,色灰褐,质硬。组织学观察:TLC的肿瘤细胞形成管状和条索状两种结构模式并相互混杂,且两者比例相当(统称为管状小叶模式)。 相似文献
6.
Binding of Cryptococcus neoformans to heterologously expressed human complement receptors. 总被引:1,自引:0,他引:1 下载免费PDF全文
S M Levitz A Tabuni T R Kozel R S MacGill R R Ingalls D T Golenbock 《Infection and immunity》1997,65(3):931-935
Previously, we demonstrated that monoclonal antibodies (MAb) directed against any of the three defined complement receptors (CR) for the third component of complement (CR1, CR3, and CR4) profoundly inhibited the binding of serum-opsonized Cryptococcus neoformans to monocyte-derived macrophages. These studies suggested either that a synergistic interaction between multiple CR was required for optimal binding of C. neoformans or that the MAb were exerting nonspecific effects (such as receptor coassociation). In the present studies, we took a novel approach to dissecting out the contributions of individual receptors to binding of a microbial pathogen. Chinese hamster ovary (CHO) cells stably transfected with human CR1, CR3, or CR4 were challenged with serum-opsonized C. neoformans. We found that CHO cells transfected with any of the three receptors bound C. neoformans, with the avidity of binding to CR3 being the greatest followed in decreasing order by CR1 and CR4. Following binding of C. neoformans to transfected CHO cells, most organisms remained surface attached only, although for each receptor a significant percentage (18.5 to 27.3%) of C. neoformans was internalized. Both C. neoformans and sheep erythrocytes that were selectively opsonized with the fragments of the third component of complement, C3b and iC3b, were bound preferentially by CHO cells transfected with CR1 and CR3, respectively. These data establish CR1, CR3, and CR4 as receptors independently capable of binding C. neoformans opsonized with fragments of C3. Moreover, our study demonstrates the usefulness of transfected cell lines as a powerful tool for identifying the contribution of individual receptors to the binding of a microbial pathogen. 相似文献
7.
Germline mutations of the CDKN2 gene in UK melanoma families 总被引:4,自引:1,他引:4
Harland M; Meloni R; Gruis N; Pinney E; Brookes S; Spurr NK; Frischauf AM; Bataille V; Peters G; Cuzick J; Selby P; Bishop DT; Bishop JN 《Human molecular genetics》1997,6(12):2061-2067
Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin
D kinase inhibitor p16, and more rarely, mutations in the gene coding for
CDK4, the protein to which p16 binds, underlie susceptibility in some
melanoma families. We have sequenced all exons of CDKN2 and analysed the
CDK4 gene for mutations in 27 UK families showing evidence of
predisposition to melanoma. Five different germline mutations in CDKN2 were
found in six families. Three of the mutations (Met53Ile, Arg24Pro and
23ins24) have been reported previously. We have identified two novel CDKN2
mutations (88delG and Ala118Thr) which are likely to be associated with the
development of melanoma, because of their co-segregation with the disease
and their likely functional effect on the CDKN2 protein. In binding assays
the protein expressed from the previously described mutation, Met53Ile, did
not bind to CDK4/CDK6, confirming its role as a causal mutation in the
development of melanoma. Ala118Thr appeared to be functional in this assay.
Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were
detected in exon 2 of CDK4, suggesting that causal mutations in this gene
are uncommon. The penetrance of these mutant CDKN2 genes is not yet
established, nor is the risk of non-melanoma cancer to gene carriers.
相似文献
8.
Romics L Dolganiuc A Velayudham A Kodys K Mandrekar P Golenbock D Kurt-Jones E Szabo G 《Journal of leukocyte biology》2005,78(6):1255-1264
Recognition of Gram-positive bacteria by Toll-like receptor 2 (TLR2) induces activation of proinflammatory pathways. In mice, sensitization with the Gram-positive Propionibacterium acnes followed by a challenge with the TLR4 ligand, lipopolysaccharide (LPS), results in fulminant hepatic failure. Here, we investigated the role of TLR2 in liver sensitization to LPS-induced injury. Stimulation of Chinese hamster ovary cells and peritoneal macrophages with heat-killed P. acnes required expression of TLR2 but not of TLR4, suggesting that P. acnes was a TLR2 ligand. Cell activation by P. acnes was myeloid differentiation primary-response protein 88 (MyD88)-dependent, and it was augmented by coexpression of CD14 in mouse peritoneal macrophages. In vitro, P. acnes behaved as a TLR2 ligand and induced TLR4 hetero- and TLR2 homotolerance in peritoneal macrophages. In vivo priming of wild-type mice with P. acnes, but not with the selective TLR2 ligands peptidoglycan and lipotheicoic acid, resulted in hepatocyte necrosis, hyperelevated serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, interferon-gamma (IFN-gamma), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1alpha, IL-6, IL-1beta, IL-18, IFN-gamma) in the liver after a LPS challenge. Furthermore, P. acnes priming sensitized TLR2-deficient (TLR2-/-) but not MyD88-/- mice to LPS-induced injury, evidenced by hepatocyte necrosis, increased levels of serum TNF-alpha, IFN-gamma, IL-6, and liver proinflammatory cytokine mRNA expression. IFN-gamma, a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2-/- and TLR9-/- but not MyD88-/- mice. These results suggest that although P. acnes triggers TLR2-mediated cell activation, TLR2-independent but MyD88-dependent mechanisms mediate in vivo sensitization by P. acnes for LPS-induced liver injury. 相似文献
9.
Skin tumors induced in mice by initiation-promotion (2 microg DMBA-2 microg
TPA) protocols were found to be under multigenic control. Eighty- one N2
mice from the cross (BALB/cAnPt x SENCARA/Pt)F1 x SENCARA/Pt that were
either solidly resistant (no papillomas) or highly susceptible (> or = 7
papillomas/mouse) were subjected to a 'genome scan' using 89 microsatellite
markers to check for associations with susceptible and resistant
phenotypes. A locus on Chr 5 (Skts4) was found to control the
susceptibility of SENCARA/Pt mice and the resistance of BALB/cAnPt mice to
papilloma formation. In addition, higher than expected linkage scores were
seen for the markers D9Mit271, D11Mit268 and D12Mit56. Further work is
required to establish whether genes determining papilloma formation are
located in these regions of the genome. In general, no evidence was seen
for loss of heterozygosity in microsatellite markers on Chrs 5, 9 and 11 in
17 microdissected papillomas from (BALB/c x SENCARA)F1 hybrid mice.
相似文献
10.
Espevik T Latz E Lien E Monks B Golenbock DT 《Scandinavian journal of infectious diseases》2003,35(9):660-664
Bacterial lipopolysaccharide (LPS) is recognized in mammals by a receptor complex composed of CD14, Toll-like receptor 4 (TLR4), and MD-2. The detailed mechanisms of how TLR4 transmits the signal from the outside to the inside of the cell remain to be elucidated. One way of studying TLR4 signaling mechanisms is to construct chimeras of TLR molecules C-terminally fused to fluorescent proteins and stably express these constructs in cells. Such constructs are functional when transfected into HEK293 epithelial cells. Confocal microscopy of TLR4 expression in live cells demonstrated pronounced expression on the plasma membrane as well in the Golgi apparatus. Studies were performed to clarify whether expression of TLR4 in the Golgi was necessary for LPS stimulation. Rapid recycling of TLR4/CD14/MD-2 complexes between the Golgi and the plasma membrane was a prominent phenomenon. In agreement with other types of plasma membrane receptors, aggregation of TLR4 by immobilized TLR4 antibodies was sufficient to induce signaling. Also, pharmacological disruption of the Golgi did not inhibit LPS induced NF-kappaB activation. Furthermore, LPS stimulation recruited the adapter molecule, MyD88, to the inside of the plasma membrane. Thus, LPS signaling commences on the plasma membrane and is independent of trafficking to the Golgi. 相似文献