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Osteopontin affects the persistence of beta-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms 总被引:4,自引:0,他引:4
Morimoto J Inobe M Kimura C Kon S Diao H Aoki M Miyazaki T Denhardt DT Rittling S Uede T 《International immunology》2004,16(3):477-488
Osteopontin (OPN) plays a pivotal role in various immune responses and inflammatory diseases. OPN is expressed in various granulomatous diseases; however, the cellular and molecular role of OPN in these diseases is not well known. We analyzed the role of OPN in a beta-glucan-induced hepatic granuloma model. First, we found that neither OPN deficiency nor overexpression of OPN affected the number and the size of hepatic granulomas at day 7, indicating that OPN is not involved in the formation of hepatic granulomas at the early stages. Importantly, OPN did not influence the liver tissue damage as defined by alanine aminotransferase and aspartate aminotransferase levels at early stages. Second, OPN deficiency resulted in the reduction of IL-12 and IFN-gamma production at early stages. Third, at late stages, OPN deficiency resulted in a decrease in the number and size of hepatic granulomas, and a reduction of liver tissue injury. This was due to the reduction of the cellular recruitment including macrophages, CD4 T cells and dendritic cells into the liver, and the reduction of tumor necrosis factor (TNF)-alpha production in the liver. In contrast, overexpression of OPN resulted in the persistence of granuloma formation. These data suggest that OPN affects the persistence of hepatic granuloma formation. Our results indicate that OPN up-regulates the production of IL-12 and IFN-gamma within the granulomas at early stages, and OPN has an additional role in the regulation of cellular recruitment and TNF-alpha production at late stages that determine the severity of liver tissue injury. 相似文献
4.
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
5.
Mouse TIMP-1, one of the tissue inhibitors of metalloproteinases important in regulating turnover of extracellular matrix in both normal and pathological tissues, was previously expressed inE. coli in an inactive, nonglycosylated state that required refolding to become functional. Due to the difficulty of renaturation, an alternative to the prokaryotic expression system was sought. Since we are interested in studying the pharmacodynamics and pharmacokinetics of TIMP locally administered by controlled delivery to mice with experimentally induced arthritis, we also needed an efficient way of producing active TIMP in large quantities. Using the pBlueBacII transfer vector, we generated a recombinant baculovirus that in Sf9 cells could express glycosylated mouse TIMP-1 to about 3 mg of active protein/liter conditioned medium. 相似文献
6.
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
7.
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
8.
HE Connor W Feniuk DT Beattie PC North AW Oxford DA Saynor PPA Humphrey 《Cephalalgia : an international journal of headache》1997,17(3):145-152
The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphona-mide), a novel 5HT1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT1B and 5HT1D receptors (pKi = 8.70.03 and 8.30.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC50 values of 0.11 and 0.07 M, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC50 value of 0.17 M; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD50 dose = 193 g kg−1 ) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID50 = 4.1 g kg−1 ). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug. 相似文献
9.
Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells 总被引:20,自引:7,他引:20 下载免费PDF全文
Nilsson SK Johnston HM Whitty GA Williams B Webb RJ Denhardt DT Bertoncello I Bendall LJ Simmons PJ Haylock DN 《Blood》2005,106(4):1232-1239
Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized critical role for Opn in regulation of the physical location and proliferation of HSCs. Within marrow, Opn expression is restricted to the endosteal bone surface and contributes to HSC transmarrow migration toward the endosteal region, as demonstrated by the markedly aberrant distribution of HSCs in Opn-/- mice after transplantation. Primitive hematopoietic cells demonstrate specific adhesion to Opn in vitro via beta1 integrin. Furthermore, exogenous Opn potently suppresses the proliferation of primitive HPCs in vitro, the physiologic relevance of which is demonstrated by the markedly enhanced cycling of HSC in Opn-/- mice. These data therefore provide strong evidence that Opn is an important component of the HSC niche which participates in HSC location and as a physiologic-negative regulator of HSC proliferation. 相似文献
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