1: Nippon Rinsho. 2005 Apr;63 Suppl 4:193-201. [Class II cytokine receptors and their ligands] [Article in Japanese] Takaoka A, Yanai H. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo. Publication Types: Review Review, Tutorial PMID: 15861656 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: Exp Hematol. 2004 Dec;32(12):1137-45. Costimulation with interleukin-4 and interleukin-10 induces mast cell apoptosis and cell-cycle arrest: the role of p53 and the mitochondrion. Bouton LA, Ramirez CD, Bailey DP, Yeatman CF, Yue J, Wright HV, Domen J, Rosato RR, Grant S, Fischer-Stenger K, Ryan JJ. Department of Biology, Virginia Commonwealth University, Richmond, Va. 23284-2012, USA. OBJECTIVE: The aim of this study was to determine the mechanism by which interleukin (IL)-4 + IL-10 costimulation regulates mast cell numbers to maintain immune homeostasis. MATERIALS AND METHODS: We employed mouse bone marrow-derived mast cells (BMMC) to measure the effects of IL-4 + IL-10 on survival and cell-cycle progression. p53-Deficient, bax-deficient, and bcl-2 transgenic BMMC were compared to wild-type cells to determine the role of these proteins in apoptosis. The molecular regulation of apoptosis and cell-cycle progression was investigated using flow cytometric analysis, RNase protection, and Western blotting. RESULTS: IL-4 + IL-10 induced BMMC apoptosis and arrest. Apoptosis was p53-dependent. Cell death was accompanied by loss of mitochondrial membrane potential, the importance of which was demonstrated by resistance to IL-4 + IL-10-mediated cell death when Bax was deleted or Bcl-2 was overexpressed. Those cells not killed by apoptosis demonstrated a p53-independent G1 cell-cycle arrest. Apoptosis and arrest may be explained by reduced IL-3 receptor signaling. CONCLUSION: Costimulation with IL-4 + IL-10 partly controls mast cell homeostasis through a delayed apoptosis and arrest program that is induced by a blockade of IL-3 receptor signaling. The delay in these negative effects would allow the protective effects of mast cell activation to occur for several days. PMID: 15588938 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Cancer Res. 2004 Oct 1;64(19):6849-53. Nitric oxide, a mediator of inflammation, suppresses tumorigenesis. Hussain SP, Trivers GE, Hofseth LJ, He P, Shaikh I, Mechanic LE, Doja S, Jiang W, Subleski J, Shorts L, Haines D, Laubach VE, Wiltrout RH, Djurickovic D, Harris CC. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA. Inflammation influences the development of cancer. The nitric oxide synthase (NOS2) is induced by inflammatory cytokines, e.g., tumor necrosis factor alpha and interleukin 1beta, and produces nitric oxide (NO*), a critical mediator of the inflammatory response. Because p53 governs NO* production by transcriptionally transrepressing NOS2, we used a genetic strategy to determine whether NO* and p53 cooperatively regulate tumorigenesis. Lymphomas developed more rapidly in p53-/-NOS2-/- or p53-/-NOS2+/- mice than in p53-/-NOS2+/+ mice that were cross-bred into a >95% C57BL6 background and maintained in a pathogen-free condition. Likewise, sarcomas and lymphomas developed faster in p53+/-NOS2-/- or p53+/-NOS2+/- than in p53+/-NOS2+/+ mice. When compared with the double knockout mice, p53-/-NOS2+/+ mice showed a higher apoptotic index and a decreased proliferation index with an increased expression of death receptor ligands, CD95-L and tumor necrosis factor-related apoptosis-inducing ligand, and the cell cycle checkpoint protein, p21(waf1), in the spleen and thymus before tumor development. Furthermore, mice deficient in both p53 and NOS2 produced a high level of anti-inflammatory interleukin 10 when compared with p53-deficient mice. These studies provide genetic and mechanistic evidence that NO* can suppress tumorigenesis. PMID: 15466171 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: Histol Histopathol. 2003 Jul;18(3):753-60. Sunburn reaction in the dorsal skin of hypotrichotic WBN/ILA-Ht rats. Okada T, Albarenque SM, Yasoshima A, Malcotti V, Katayama K, Uetsuka K, Nakayama H, Doi K. Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. The dorsal skin responses to a single irradiation with a high-dose of UVB (10kJ/m2) were examined histologically and immunohistochemically in UVB-sensitive Wistar-derived hypotrichotic WBN/ILA-Ht rats (HtRs). Sunburn cells (SBCs) which were characterized by pyknotic nuclei and eosinophilic cytoplasm and had ultrastructual characteristics of apoptotic cells were first observed in the epidermis at 3 hours (h) after irradiation. The number peaked at 6 h, and then decreased rapidly. The expressions of p53 protein, which is known to be closely related to the formation of SBCs, and of p21 protein, which is one of the transcriptional target genes of p53, were immunohistochemically detected, and their labeling index (LI) in the epidermis peaked at 12 to 24 h (p53) or at 24h (p21) after irradiation. On the other hand, proliferating cell nuclear antigen (PCNA)-LI in keratinocytes was significantly lower than the control group at 6 h after irradiation and thereafter it increased and became significantly higher than the control group from 24 to 48 h. At 48 h, moderate hyperplasia with moderate numbers of mitotic keratinocytes was first observed in the epidermis. In the dermis, mild edema developed from 12 to 36 h and it accompanied mild lymphocyte infiltration at 36 h. Judging from the present results, it was suggested that some factors other than p53 might be involved in SBC formation, and that p53 might induce p21 protein and play an important role in cell growth arrest in keratinocytes after UVB irradiation. PMID: 12792887 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 5: Cancer Immunol Immunother. 2002 Nov;51(9):513-9. Epub 2002 Sep 6. Accumulation of CD45RO(+) cells in peritoneal carcinomatous fluid favours survival of ovarian carcinoma patients. Kryczek I, Grybos M, Dlubek D, Klimczak A, Rabczynski J, Lange A. Department of Clinical Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigl Str, 53-114 Wroclaw, Poland. lange@iitd.pan.wroc.pl In 44 patients with advanced ovarian carcinoma (OC) a fraction of CD45RO(+) lymphocytes in the blood and peritoneal carcinomatous fluid (PCF) was investigated. Thirty-one patients received cisplatinum with cyclophosphamide +/- doxorubicin. This group was followed from 2.2 to 9 years (mean: 45 months). In 23 out of 31 patients, the percentage of CD45RO(+) lymphocytes was higher in the PCF than in the blood samples. Patients with these higher lymphocyte levels experienced longer survival than those who did not show any excess of CD45RO(+) lymphocytes in PCF ( P=0.02). This was further verified by the use multivariate Cox analysis which included an assessment of the percentage of CD45RO(+) lymphocytes in PCF, age, FIGO status, histology, treatment (CAP or CP) and residual disease (RD) post-surgery. This analysis revealed that two factors had an independent power of prediction: RD ( P=0.02) and the percentage of CD45RO(+) cells in PCF ( P=0.04). Therefore, CD45RO(+) lymphocytes were studied in further detail in a group of 20 patients. This study revealed that PCF CD45RO(+) lymphocytes were characterized by: (1) a higher proportion of cells co-expressing activation markers (HLA-DR, CD28) and higher levels of mRNA for CXC chemokines (IP-10, IL-8) and for IL-10, but with lower levels for IL-2; (2) higher levels of Ki67, bcl-2 and p53 mRNA as compared to those in blood. In conclusion, in the present study it was found that an accumulation of activated CD45RO(+) cells in PCF had a beneficial effect on the survival of patients receiving platinum-based chemotherapy. PMID: 12357323 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 6: Carcinogenesis. 2001 Apr;22(4):665-71. Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Sturlan S, Oberhuber G, Beinhauer BG, Tichy B, Kappel S, Wang J, Rogy MA. Department of General Surgery, University of Vienna, Wahringer Gurtel 18-20, 1090 Vienna, Austria. Interleukin-10-deficient mice develop colitis and colorectal cancer similar to the inflammatory bowel disease associated cancer in humans. The aim of this study was to identify possible mutations of oncogenes and tumour suppressor genes involved in tumorigenesis in Interleukin-10 (IL-10)-deficient mice. Twenty colon carcinomas from IL-10-deficient mice were screened for mutations in the K-ras and p53 genes by 'cold' single-strand-conformation polymorphism. Immunohistochemical staining was performed to detect mutations in the proteins P53, APC and MSH2, and the transforming growth factor beta type II receptor. Microsatellite instability was analysed at eight chromosomal loci and plasma levels of transforming growth factor beta1 (TGF-beta1) were also measured. At 9 weeks, 14% of the animals developed colorectal cancer, and at 10-31 weeks the incidence of carcinoma was 65%. No mutations were detected in the analysed oncogene and tumour suppressor genes. Plasma TGF-beta1 levels in IL-10-deficient mice 10-31 weeks old were higher than in wild-type littermates e.g. 45.7 +/- 4.6 ng/ml versus 19.8 +/- 4.5 ng/ml (P<0.01). No alterations in K-ras, p53, APC: and Msh2 genes suggests that other genes are involved in the development of these tumours. Elevated TGF-beta1 plasma levels correspond to the high incidence of dysplasia and cancer. Normal expression of the TGF-beta II receptors hints at genetic alterations in other members of the TGF-beta receptor signal transduction pathway. PMID: 11285204 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 7: Immunology. 1999 Sep;98(1):47-54. Activation sensitizes human memory B cells to B-cell receptor-induced apoptosis. Berard M, Casamayor-Palleja M, Billian G, Bella C, Mondiere P, Defrance T. INSERM U 404 'Immunite et Vaccination', Avenue Tony Garnier, Lyon, France. The outcome of antigen receptor (B-cell receptor; BCR) ligation on B-cell survival can be influenced by multiple parameters. They are linked to the physical properties of the antigen itself, the maturational stage of the cells and the costimuli provided by different components of the innate and acquired immunity. Here we report that apoptosis prevails over stimulation when a BCR agonist is applied to human memory B cells which have been preactivated by CD40 ligand or anti-immunoglobulin antibodies. The susceptibility of activated memory B cells to BCR-induced killing is correlated with their enhanced expression of the transcripts encoding the pro-apoptotic molecules Bax, c-Myc and p53. The BCR-mediated apoptosis of activated memory B cells does not require extensive cross-linking of the antigen receptors and relies neither on engagement of the FcgammaRII nor on the Fas/Fas ligand (Fas-L) system. Our findings suggest that activation stimuli open the BCR-induced apoptotic pathway in memory B cells. Therefore we propose that the concept of activation-induced cell death (AICD), originally described for T cells, also applies to mature B lymphocytes. The functions fulfilled by the AICD of mature B cells in the regulation of B-cell responses are discussed. PMID: 10469233 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 8: J Immunol. 1999 May 15;162(10):6122-31. TNF-alpha and IL-10 modulate the induction of apoptosis by virulent Mycobacterium tuberculosis in murine macrophages. Rojas M, Olivier M, Gros P, Barrera LF, Garcia LF. Grupo de Inmunologia Celular e Inmunogenetica, Laboratorio Central de Investigaciones, Centro de Investigaciones Medicas. Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia. The Bcg/Nramp1 gene controls early resistance and susceptibility of macrophages to mycobacterial infections. We previously reported that Mycobacterium tuberculosis-infected (Mtb) B10R (Bcgr) and B10S (Bcgs) macrophages differentially produce nitric oxide (NO-), leading to macrophage apoptosis. Since TNF-alpha and IL-10 have opposite effects on many macrophage functions, we determined the number of cells producing TNF-alpha and IL-10 in Mtb-infected or purified protein derivative-stimulated B10R and B10S macrophages lines, and Nramp1+/+ and Nramp1-/- peritoneal macrophages and correlated them with Mtb-mediated apoptosis. Mtb infection and purified protein derivative treatment induced more TNF-alpha+Nramp1+/+ and B10R, and more IL-10+Nramp1-/- and B10S cells. Treatment with mannosylated lipoarabinomannan, which rescues macrophages from Mtb-induced apoptosis, augmented the number of IL-10 B10R+ cells. Anti-TNF-alpha inhibited apoptosis, diminished NO- production, p53, and caspase 1 activation and increased Bcl-2 expression. In contrast, anti-IL-10 increased caspase 1 activation, p53 expression, and apoptosis, although there was no increment in NO- production. Murine rTNF-alpha induced apoptosis in noninfected B10R and B10S macrophages that was reversed by murine rIL-10 in a dose-dependent manner with concomitant inhibition of NO- production and caspase 1 activation. NO- and caspase 1 seem to be independently activated in that aminoguanidine did not affect caspase 1 activation and the inhibitor of caspase 1, Tyr-Val-Ala-Asp-acylooxymethylketone, did not block NO- production; however, both treatments inhibited apoptosis. These results show that Mtb activates TNF-alpha- and IL-10-dependent opposite signals in the induction of macrophage apoptosis and suggest that the TNF-alpha-IL-10 ratio is controlled by the Nramp1 background of resistance/susceptibility and may account for the balance between apoptosis and macrophage survival. PMID: 10229855 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 9: Int J Cancer. 1997 Jul 29;72(3):398-402. Interleukin-10 expression and cytotoxic-T-cell response in Epstein-Barr-virus-associated nasopharyngeal carcinoma. Yao M, Ohshima K, Suzumiya J, Kume T, Shiroshita T, Kikuchi M. First Department of Pathology, School of Medicine, Fukuoka University, Jonan-ku, Japan. Interleukin-10 (IL-10) is an inhibitory cytokine produced by various cell types. It exhibits strong sequence homology to BCRF-1 (viral IL-10, vIL-10), an open reading frame in the Epstein-Barr-virus (EBV) genome. Using in situ hybridization (ISH), polymerase chain reaction (PCR) and immunohistochemistry, we checked 41 cases of nasopharyngeal carcinoma (NPC), to study the presence of EBV in the tumor cells, as well as to clarify the relationship between IL-10 expression of the tumor cells and the response of cytotoxic T cells. IL-10 expression was studied by immunohistochemistry; as a result, 29 of 41 cases expressed EBER-1 RNA of EBV by ISH. In addition, 19 of the 29 with EBV and 9 of 12 without EBV cases expressed IL-10 in the tumor cells. The number of cytotoxic T cells increased in the tumor tissue, and the increase in the intratumoral stroma was stronger than in the remaining normal epithelia. The number of cytotoxic T cells also significantly increased in the cases with EBV. On the other hand, in the IL-10-positive series, the number of cytotoxic T cells decreased significantly more than in IL-10-negative series. In view of the established inhibitory effects of IL-10, expression of IL-10 may therefore be one of the mechanisms for NPC cells as well as EBV to counter local immune defense. However, we could not conclude whether or not IL-10 expression was directly induced by EBV. PMID: 9247280 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 10: Bull Cancer. 1994;81 Suppl 1:3s-13s. [Malignant melanoma] [Article in French] Baume D. Publication Types: Congresses Review Review, Tutorial PMID: 7727853 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------