Acquired Immunodeficiency Syndrome: Mori S

Katano H, Sata T, Mori S. · Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. · Curr Top Microbiol Immunol. · Pubmed #11443857 No free full text.

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Murakami-Mori K, Mori S, Bonavida B. · Department of Microbiology and Immunology, UCLA School of Medicine 90095, USA. · Adv Cancer Res. · Pubmed #10547670 No free full text.

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Katano H, Sato Y, Hoshino S, Tachikawa N, Oka S, Morishita Y, Ishida T, Watanabe T, Rom WN, Mori S, Sata T, Weiden MD, Hoshino Y. · Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo 162-8640, Japan. · Microbes Infect. · Pubmed #18024124 links to  free full text

Abstract: Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5' long terminal repeat (LTR) deletion, but the 3' LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case.

Mori S, Murakami-Mori K, Nakamura S, Bonavida B. · Department of Microbiology, Immunology, and Molecular Genetics, UCLA School of Medicine, University of California, Los Angeles, CA 90095, USA. · Int J Oncol. · Pubmed #11894131 No free full text.

Abstract: Fas engagement rapidly induces formation of the death-inducing signaling complex (DISC) that consists of Fas, FADD and pro-caspase-8. Activated caspase-8 at the DISC directly activates downstream caspases, resulting in induction of apoptosis of the independent mitochondria. In this study, we have obtained evidence demonstrating that Fas-mediated apoptosis in AIDS-KS cells takes place in a mitochondria-dependent manner. FADD and pro-caspase-8 were detected in immunoprecipitates with anti-Fas antibody in anti-Fas mAb (CH-11)-treated Hut 78, a typical Fas-sensitive cell line. On the other hand, DISC formation by CH-11 was markedly reduced in AIDS-KS cells. In addition, CH-11-induced activation of caspase-8-like protease in AIDS-KS cells was much less pronounced compared with that in Hut 78; however, a caspase-8 inhibitor, zIETD-fmk, completely blocked the apoptosis. Further, a caspase-9 inhibitor, zLEHD-fmk, markedly inhibited Fas-mediated apoptosis in AIDS-KS cells. Several apoptotic stimuli induce mitochondria activation allowing cytochrome c release from the mitochondria. In the apoptosome, cytochrome c and Apaf-1 activate caspase-9 which subsequently leads to the activation of caspase-3. In AIDS-KS cells, CH-11 triggered cytochrome c release, an event which was inhibited by zIETD-fmk. Further, a caspase-3 inhibitor, zDEVD-fmk completely inhibited the apoptosis. Altogether, the present data provide evidence that the Fas signal in AIDS-KS cells is preferentially transduced through the mitochondria-dependent pathway, which is initiated by caspase-8 activation.

Suda T, Katano H, Delsol G, Kakiuchi C, Nakamura T, Shiota M, Sata T, Higashihara M, Mori S. · Department of Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. · Pathol Int. · Pubmed #11696169 No free full text.

Abstract: Multicentric Castleman's disease (MCD) is a clinicopathologically defined entity characterized by systemic lymphadenopathy with unique pathomorphology such as angiosclerosis, blood vessel proliferation in and around follicles, and plasmacytosis. While its pathogenesis has remained unclarified for many years, identification of the human herpesvirus 8 (HHV-8) in at least some MCD cases has opened new perspectives in this field. Because previous reports have described many inconsistencies regarding HHV-8 positivity in MCD, we intended to clarify this issue by the introduction of more convincing methodologies. For this investigation, we introduced two antibodies produced in our laboratories that recognize a latent gene product ORF73 and a lytic gene product ORF59, together with two well-recognized methods, in situ hybridization for the detection of lytic phase transcript T1.1/nut-1, and genomic polymerase chain reaction (PCR). Eighty-two cases of MCD were collected from Japan (n = 75) and France (n = 7). In three cases, the patients were suffering from acquired immunodeficiency syndrome (AIDS). Immunohistochemistry and in situ hybridization showed identical results: only three out of 82 cases were positively stained, and all the positive cases were found to be the patients with AIDS. Genomic PCR was done in 43 cases, and only one case produced positive results: the only AIDS case among the 43 cases studied by genomic PCR. Histopathologically, the HHV-8-positive cases showed the highest intensity of angiosclerosis and germinal center / perifollicular vascular proliferation, while plasmacytosis was not severe in the HHV-8-positive cases. Some of the HHV-8-negative MCD cases displayed similar histopathology, but at a far less intense level, except for the plasmacytosis. These results suggest that: (i) all three of the HHV-8-positive MCD patients in the present group are the patients with AIDS; and (ii) HHV-8-positive MCD patients develop typical but marked angiosclerosis and vascular proliferation that might be differentiated from HHV-8-negative MCD patients, who showed far less intense changes.

Murakami-Mori K, Mori S, Nakamura S. · Department of Pathology I, Kumamoto University School of Medicine, Kumamoto, 860-0811, Japan. · Biochem Biophys Res Commun. · Pubmed #10543991 No free full text.

Abstract: AIDS-associated Kaposi's sarcoma (KS) is a cytokine-mediated tumor, at least in the early stages of this disease; however, there is at present no definitive consensus regarding the exact role of intracellular signaling pathways involved in growth of KS cells. We found that KS cell growth factors oncostatin M, sIL-6R/IL-6, TNFalpha, and IL-1beta all activate ERK1/2, and selective blockage of this kinase by PD98059 resulted in a profound inhibition of the cytokine-induced KS cell growth. Concurrently with activation of ERK1/2, these growth factors phosphorylated and activated p38MAPK. The selective inhibition of p38MAPK by SB203580 prominently enhanced the cytokine-induced proliferation of KS cells, thereby indicating that p38MAPK has a negative feedback on mitogenic signals. As these KS cell growth factors lead to simultaneous activation of ERK1/2 and p38MAPK signaling pathways, the concerted effects of these kinase activities may well determine the intensity of cellular proliferative responses to these growth factors.

Mori S, Murakami-Mori K, Nakamura S, Ashkenazi A, Bonavida B. · Department of Microbiology and Immunology, University of California School of Medicine, Los Angeles 90095, USA. · J Immunol. · Pubmed #10228045 links to  free full text

Abstract: Kaposi's sarcoma (KS) is the most frequent malignancy associated with HIV infection (AIDS-KS), a complication that leads to high mortality and morbidity. AIDS-KS cells are resistant to killing by chemotherapeutic drugs/NK cells and Fas-induced apoptosis, suggesting that the acquisition of antiapoptotic characteristics by AIDS-KS cells may contribute to their prolonged survival. Apo-2 ligand (Apo-2L)/TNF-related apoptosis-inducing ligand, a new member of the TNF family, has been identified as an apoptosis-inducing molecule. In this study we examined the sensitivity of 10 different AIDS-KS isolates to Apo-2L-mediated cytotoxicity. AIDS-KS cells were relatively resistant to Apo-2L; however, Apo-2L and actinomycin D (Act D) used in combination synergistically potentiated the induction of cell death in nine of the 10 isolates. Apo-2L induced apoptosis in >80% of AIDS-KS cells pretreated with Act D. The caspase inhibitors, zIETD-fmk and zDEVD-fmk, inhibited apoptosis in AIDS-KS by sApo-2L, suggesting that caspase 3-like and caspase 8 or 10 activities are essential for Apo-2L-mediated apoptosis. Act D treatment of AIDS-KS cells markedly and selectively down-regulated Bcl-xL expression, while the expressions of decoy receptors 1 and 2, Bax, cellular FLICE (Fas-associated death domain protein-like IL-1-converting enzyme) inhibitory protein, FADD (Fas-associated death domain protein), procaspase 8, and p53 were not affected. These findings suggest the possible involvement of Bcl-xL in Act D-induced sensitization of AIDS-KS cells to Apo-2L-mediated apoptosis. Furthermore, Act D did not sensitize PBMC or fibroblast cells to Apo-2L. Thus, Apo-2L and Act D used in combination may be of therapeutic value in the treatment of AIDS-KS.

Murakami-Mori K, Mori S, Bonavida B, Nakamura S. · Department of Microbiology and Immunology, University of California, School of Medicine, Los Angeles 90095, USA. · J Immunol. · Pubmed #10092829 links to  free full text

Abstract: TNF-alpha is a key pathogenic mediator of infectious and inflammatory diseases. HIV infection stimulates and dysregulates the immune system, leading to abnormal production of TNF-alpha. Despite its cytotoxic effect on some tumor cell lines, TNF-alpha functions as a growth stimulator for Kaposi's sarcoma (KS), a common malignancy in HIV-infected patients. However, signaling pathways linked to TNF-alpha-induced mitogenic responses are not well understood. We found that extracellular signal-regulated kinases 1 and 2 (ERK1/2) in KS cells were significantly activated by TNF-alpha through tyrosine/threonine phosphorylation. Using neutralizing anti-TNFR-I and TNFR-II mAbs, we have now obtained evidence that TNF-alpha-induced KS cell growth and ERK1/2 activation are mediated exclusively by TNFR-I, not by TNFR-II. A selective inhibitor for ERK1/2 activator kinases, PD98059, profoundly inhibited not only the activation of ERK1/2, but also the TNF-alpha-induced KS cell proliferation. We therefore propose that the TNFR-I-ERK1/2 pathway plays a pivotal role in transmitting to KS cells the mitogenic signals of TNF-alpha. TNFR-I possesses no intrinsic kinase activity, suggesting that TNFR-I-associated proteins may provide a link between TNFR-I and ERK1/2 activation. We found that actinomycin D treatment of KS cells selectively abolished expression of mitogen-activated protein kinase-activating death domain protein (MADD), a novel TNFR-I-associated death domain protein. TNF-alpha failed to induce ERK1/2 activation in the actinomycin D-treated cells. MADD may couple TNFR-I with the ERK1/2 signaling pathway required for KS cell proliferation.