Synergistic Cytotoxicity of Rana catesbeiana Ribonuclease and IFN-γ on Hepatoma Cells

Abstract Background & Aims: Hepatocellular carcinoma (HCC) displays a particular resistance to conventional cytostatic agents. Therefore, alternative treatment strategies focus on novel substances exhibiting anti-neoplastic and/or immunomodulatory activity enhancing for example Natural Killer (NK) cell anti-tumor reactivity. However, the tumor-associated ligands engaging activating NK cell receptors are largely unknown. Exceptions are the NKG2D ligands (NKG2DL) of the MIC and ULBP protein families, which potently stimulate NK cell responses. We studied the consequences of proteasome inhibition with regard to direct and NK cell-mediated effects against HCC. Methods: Primary human hepatocytes (PHH) from different donors, hepatoma cell lines and NK cells were exposed to Bortezomib. Growth and viability of hepatoma cells and PHH as well as immunomodulatory effects including alterations of NKG2DL expression on hepatoma cells, specific induction of NK cell cytotoxicity and IFN-γ production were investigated. Results: Bortezomib treatment inhibited hepatoma cell growth with IC50 values between 2.4 and 7.7 nanomol/liter. These low doses increased MICA/B mRNA levels and total and cell surface protein expression in hepatoma cells, which stimulated cytotoxicity and IFN-γ production of cocultured NK cells. Importantly, while IFN-γ production of NK cells was concentration-dependently reduced, low-dose Bortezomib neither induced NKG2DL expression or cell death in PHH nor altered NK cell cytotoxicity. Conclusions: Low-dose Bortezomib mediates a specific dual anti-tumor effect in HCC by inhibiting tumor cell proliferation and by priming hepatoma cells for NK cell anti-tumor reactivity. Our data suggest the clinical evaluation of Bortezomib treatment in HCC, especially in combination with immunotherapeutic approaches like adoptive NK cell transfer.

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Vesicular system associated with spermiogenesis of bullfrog

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128377 ◽

1987 ◽

Vol 45 ◽

pp. 818-819

Author(s):

K. C. Liu ◽

S. F. Tsay

Keyword(s):

Electron Microscopy ◽

Microscopic Study ◽

Electron Microscopic Study ◽

Reproductive System ◽

Seminiferous Tubule ◽

Rana Catesbeiana ◽

Routine Procedure ◽

Electron Microscopic ◽

Twisted Tubules ◽

Electron Lucent

In the histologic and electron microscopic study of the male reproductive system of bullfrog, Rana catesbeiana, a vesicular system associated with spermiogenesis was observed. It appeared in the lumenal space of the seminiferous tubule (Fig. 1), in the heads of spermatids (Fig. 2), associated with the chromatins of the spermatid (Fig. 4). As deduced from sections, this vesicular system consisted of vesicles of various size or a large group of waving and twisted tubules (Fig. 3), After routine procedure of treatment for electron microscopy, the lumens of both of the vesicles and tubules were electron lucent.In human, vesicles and vesicular system associated with reproductive cell and tissue were reported. In abnormal spermiogenesis, flower-like body, actually vesicles, and giant vesicle associated with the head of spermatid were observed. In both cases the number of vesicle was limited from a single one to a few.

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Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100160297 ◽

1990 ◽

Vol 48 (3) ◽

pp. 548-549

Author(s):

T. A. Stewart ◽

D. Liggitt ◽

S. Pitts ◽

L. Martin ◽

M. Siegel ◽

...

Keyword(s):

Type I Diabetes ◽

Disease Process ◽

Class Ii ◽

Class I ◽

Type I ◽

Aberrant Expression ◽

Mhc Molecules ◽

Endogenous Insulin ◽

Class Ii Mhc ◽

Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

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