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91.
Autocrine motility factor (AMF) is one of the motility cytokines regulating tumor cell migration, therefore identification
of the signaling pathway coupled with it has critical importance. Previous studies revealed several elements of this pathway
predominated by lipoxygenase-PKC activations but the role for tyrosine kinases remained questionable. Motility cytokines frequently
have mitogenic effect as well, producing activation of overlapping signaling pathways therefore we have used B16a melanoma
cells as models where AMF has exclusive motility effect. Our studies revealed that in B16a cells AMF initiated rapid (1–5
min) activation of the protein tyrosine kinase (PTK) cascade inducing phosphorylation of 179, 125, 95 and 40/37 kD proteins
which was mediated by upstream cyclo- and lipoxygenases. The phosphorylated proteins were localized to the cortical actin-stress
fiber attachment zones in situ by confocal microscopy. On the other hand, AMF receptor activation induced significant decrease
in overall serine-phosphorylation level of cellular proteins accompanied by serine phosphorylation of 200, 90, 78 and 65 kd
proteins. The decrease in serine phosphorylation was independent of PTKs, PKC as well as cyclo- and lipoxygenases. However,
AMF induced robust translocation of PKCα to the stress fibers and cortical actin suggesting a critical role for this kinase
in the generation of the motility signal. Based on the significant decrease in serine phosphorylation after AMF stimulus in
B16a cells we postulated the involvement of putative serine/threonine phosphatase(s) upstream lipoxygenase and activation
of the protein tyrosine kinase cascade downstream cyclo- and lipoxygenase(s) in the previously identified autocrine motility
signal.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
92.
David P. Shrayer Bernard Cole Vincent J. Hearing Stanley F. Wolf Harold J. Wanebo 《Clinical & experimental metastasis》1999,17(1):73-80
Interleukin (IL)-12 can activate cytotoxic lymphocytes, stimulate natural killer cell activity, induce the production of INF- and inhibit the development of various experimental tumors. We previously demonstrated that immunotherapy of melanoma bearing mice with an irradiated melanoma vaccine (IMV) coupled with IL-2 or GM-CSF had beneficial effects against primary melanoma growth and against subsequent spontaneous metastasis. We also had found that treatment of melanoma bearing mice with IL-12 (300 ng/day) for 4 weeks inhibited the development of primary melanoma tumors in 40% of mice. The purpose of this study was to investigate the efficacy of combined therapy of experimental melanoma with an IMV prepared from B16F10 melanoma cells coupled with IL-12 treatment. C57BL/6 mice were challenged subcutaneously in the tail with B16F10 melanoma cells and by the 45th day, more than 50% of the mice had developed visible primary melanoma tumors at the injection site. Subsequent immunotherapy of mice with IMV, when coupled with IL-12, provided partial inhibition of primary melanoma tumor growth. Optimal results against primary tumor growth were observed when IMV therapy was coupled with IL-12 at a dose of 50 ng/day. Combination of IMV with IL-12 at a dose of 100 ng/day significantly reduced melanoma metastasis to the lungs compared with control mice, and an improvement in mean survival time was observed in mice treated with a combination of IMV with IL-12 (300 ng/day). 相似文献
93.
A case of Klinefelter's Syndrome with a paracentric inversion in chromosome 12 is described. The karyotype was determined to be 47, XXY, inv(12)(q15q24) and the significance of the breakpoints on chromosome 12 is discussed. 相似文献
94.
结核分枝杆菌Ag85B与IL-12基因真核共表达质粒的构建及表达 总被引:3,自引:1,他引:3
目的 :构建结核分枝杆菌Ag85B和鼠IL 12基因的共表达载体pBud85B IL12。方法 :将结核分枝杆菌Ag85B基因和鼠IL 12基因同时克隆入含多启动子的共表达载体pBudCE4 .1中 ,构建真核共表达质粒pBud85B IL12。以pBud85B IL12转染COS 7细胞 ,通过RT PCR及ELISA方法检测目的基因的表达。结果 :在COS 7细胞中同时可检测到Ag85B和IL12的表达。结论 :pBud85B IL12共表达质粒的成功构建 ,为对其免疫原性、免疫反应性及免疫保护作用的进一步研究奠定了基础 相似文献
95.
Lam GK Liao HX Xue Y Alam SM Scearce RM Kaufman RE Sempowski GD Haynes BF 《Journal of clinical immunology》2005,25(1):41-49
CD7 is an immunoglobulin superfamily molecule expressed on T, NK, and pre-B lymphocytes. Previous studies have demonstrated a role for CD7 in T- and NK-cell activation and cytokine production. Recently, an epithelial cell secreted protein, K12, was identified as a CD7 ligand. Although CD7 is expressed intrathymically, it is not known if K12 is produced in human thymus. To determine roles that K12 might play in the human thymus, we analyzed expression of K12 in human thymocytes, thymic epithelial cells (TE), and thymic fibroblasts. We found that recombinant human K12 bound strongly to soluble hCD7, with a Keq of 37.6×10–9M, and this interaction was inhibited by a novel antihuman K12 monoclonal antibody (K12-A1). K12 mRNA was detected by RT–PCR and northern analysis in human TE and thymic fibroblasts, but not in human thymocytes. Expression of K12 in TE cells was upregulated by IFN- . Taken together, these data demonstrated that K12 is produced by human TE cells and thymic fibroblasts, and is regulated in thymus by IFN- . These data suggest a role for thymic microenvironment-produced K12 in regulation of thymocyte signaling and cytokine release, particularly in the setting of thymus pathology where IFN- is upregulated such as myasthenia gravis. 相似文献
96.
Iwasaki M Yu WG Uekusa Y Nakajima C Yang YF Gao P Wijesuriya R Fujiwara H Hamaoka T 《International immunology》2000,12(5):701-709
While IL-12 administration induces tumor regression through stimulating T cells in tumor-bearing mice, this IL-12 effect is observed in some but not all tumor models. The present study aimed to compare IL-12 responsiveness of T cells from tumor-bearing mice in IL-12-responsive (CSA1M and OV-HM) and -unresponsive (Meth A) tumor models. Tumor regression in IL-12-responsive tumor models required the participation of T cells, but not of NK1.1(+) cells. Because a NK1.1(+) cell population was the major producer of IFN-gamma, comparable levels of IFN-gamma production were induced in IL-12-responsive and -unresponsive tumor-bearing mice. This indicates that the amount of IFN-gamma produced in tumor-bearing individuals does not correlate with the anti-tumor efficacy of IL-12. In contrast, IL-12 responsiveness of T cells differed between the responsive and unresponsive models: purified T cells from CSA1M/OV-HM-bearing or Meth A-bearing mice exhibited high or low IL-12 responsiveness respectively, when evaluated by the amounts of IFN-gamma produced in response to IL-12. T cells from CSA1M- or OV-HM-bearing but not from Meth A-bearing mice exhibited enhanced levels of mRNA for the IL-12 receptor (IL-12R). These results indicate that a fundamental difference exists in IL-12 responsiveness of T cells between IL-12-responsive and -unresponsive tumor models, and that such a difference is associated with the expression of IL-12R on T cells. 相似文献
97.
DNA is a complex macromolecule whose immunological properties vary with sequence and structure. To determine whether DNA can inhibit immune responses, the effects of mammalian DNA and synthetic phosphodiester (Po) and phosphorothioate (Ps) oligonucleotides (ODNs) on IL-12 production were tested using murine macrophages. With bacterial DNA as a stimulant, calf thymus DNA and human placenta DNA blocked IL-12 production by splenic and bone marrow macrophages. A (dG)(30) Po ODN and all single-base Ps 30 mer ODNs were also effective inhibitors. The Ps ODNs also blocked IL-12 production induced by lipopolysaccharide (LPS) and a stimulatory Ps ODN. With the J774 cell line, single-base Ps ODNs inhibited IL-12 production induced by bacterial DNA, LPS, and a stimulatory Ps ODN. Together, these results indicate that DNA has inhibitory properties, suggesting that mammalian DNA could limit immune activation during inflammation and counteract the effects of bacterial DNA. 相似文献
98.
Tieno Germann Maurice K. Gately David S. Schoenhaut Michael Lohoff Frank Mattner Susanne Fischer Shen-Chu Jin Edgar Schmitt Erwin Rüde 《European journal of immunology》1993,23(8):1762-1770
At least two subsets of CD4+ T helper cell lymphocytes termed Th1 and T h, 2 exist in the mouse and probably in humans. They are characterized by the secretion of different lymphokines and by their functional behavior. Dysregulated expansion of one or the other subset may be one reason for the development of certain diseases. Thus, it is of importance to define the signals involved in the differentiation and activation of the two Th cell subsets. It is known and has been confirmed in this report that the cytokine interleukin (IL)-1 acts onTh2 cells but not on Th1 cells. We now report that a previously identified cytokine which was provisionally termed T cell stimulating factor is identical with IL-12 and exhibits a reciprocal behaviour to IL-1. IL-12 has several effects on Th1 cells. It can induce the proliferation of certain Th1 cells in combination with IL-2. Synthesis of interferon (IFN)-γ by Th1 cells can be triggered by IL-2 plus IL-12. In contrast to the IFN-γ production observed after T cell receptor (TcR) CD3 stimulation of Th1 cells with lectin Concanavalin A the IFN-γ production induced by IL-12+IL-2 is insensitive to the immunosuppressive drug cyclosporin A. Furthermore, IL-12 enhances the TcR/CD3-induced synthesis of IFN-γ of several Th1 clones. Finally, IL-12 (+ IL-2) induces homotypic cell aggregation of Th1 clones. This type of cell aggregation depends on the participation of LFA-1 and ICAM-1 molecules. In all activation systems with Th1 cells no effect of IL-1 was demonstrable. In contrast, only IL-1 but not IL-12 served as a co-stimulatory signal for several Th2 cell lines activated via the TcR/CD3 complex. 相似文献
99.
Regional cerebral blood flow is measured by monitoring the clearance from the brain of the gamma emitting radioisotope 133Xe following an intracarotid artery bolus injection. On-line data analysis, which is performed on a PDP digital computer, involves exponential stripping to isolate grey and white matter flows and integration of the clearance curves to infinity to enable the mean flow to be calculated. The data is displayed in real time and stored on the PDP 12 Linc tapes as a permanent record. 相似文献
100.
Ferdinand von Meyenn Martin Schaefer Heike Weighardt Stefan Bauer Carsten J. Kirschning Hermann Wagner Tim Sparwasser 《Immunobiology》2006,211(6-8):557
Recognition of mycobacteria by the innate immune system is essential for the development of an adaptive immune response. Mycobacterial antigens stimulate antigen presenting cells (APCs) through distinct Toll-like receptors (TLRs) resulting in rapid activation of the innate immune system. The role of TLRs during infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been evaluated for TLR2 and TLR4 only. Surprisingly, despite the fact that immune stimulatory CpG-motifs have been originally derived from BCG, for the vaccine strain the role of TLR9 has not been addressed before. To identify the set of TLRs involved in the recognition of BCG, we infected bone marrow-derived macrophages and bone marrow-derived dendritic cells (Flt3-ligand generated DCs) from TLR2, TLR3, TLR4, TLR7, TLR9, MyD88 knockout, TLR2/4 and TLR2/4/9 multiple knockout mice. The degree of activation and stimulation was determined by TNFα, IL-6 and IL-12p40 ELISA. Activation of DCs was measured by surface expression of the costimulatory molecule CD86. We observed the most dramatic reduction of the inflammatory response for TLR2-deficient antigen presenting cells. Both macrophages and DCs produce markedly decreased amounts of TNFα and IL-6 in the absence of TLR2 whereas no significant reduction could be observed for TLR3, 4, 7, 9 single TLR-knockouts. However, IL-12 production in DCs appears not exclusively dependent on TLR2 and only in TLR2/4/9-deficient DCs BCG-induced IL-12 is reduced to background levels. Similarly, up-regulation of CD86 is abolished only in TLR2/4/9-deficient DCs supporting a role of TLR9 in the recognition of M. bovis BCG by murine dendritic cells. 相似文献