NZB mice develop an age-related malignant expansion of a subset of B cells, B-1 cells, with autocrine production of IL-10. IL-10, a pleiotropic cytokine with anti-inflammatory properties, is a potent growth and survival factor for malignant B cells. To further examine the in vivo requirement for IL-10 in the development and expansion of malignant B-1 clones in NZB mice, we developed a strain of homozygous IL-10 knockout (KO) mice on an NZB background. The NZB IL-10 KO mice develop peritoneal B-1 cells with approximately the same frequency as heterozygous and wild-type littermates. In contrast, the development of malignant B-1 cells in the peripheral blood and spleen, observed in wild-type NZB, rarely occurred in the NZB IL-10 KO. Phenotypic analysis of surface marker expression in splenic B cells indicated that, in contrast to the NZB with malignant B-1 splenic lymphoma, the surface marker expression of NZB IL-10 KO splenic B cells indicated that the majority of the B cells were typical B-2 cells. In the absence of IL-10, spontaneously activated B cells and antiapoptotic gene expression were reduced and lymphoma incidence was decreased. These results indicate that IL-10 is a critical factor for the progression of this B-cell malignant disease.
Cytokines such as tumor necrosis factor (TNF)-alpha and Interleukin (IL)-10 play significant roles in autoimmunity and transplantation tolerance. Allelic polymorphisms that occur in the regulatory regions of these cytokine genes are closely associated with acute and chronic transplant rejection. The presence of a G-to-A polymorphism at position -308 in the promoter region of the TNF-alpha gene can increase transcription six- to sevenfold. Likewise, the G-A polymorphism at position -1082 of the IL-10 promoter results in lower levels of IL-10 protein. Accordingly, a genotype that dictates the production of high levels of TNF-alpha with low IL-10 capabilities is most likely to generate an inflammatory environment that is less receptive to the transplant. The potential for determining a patient's haplotype before transplantation may be an effective way of monitoring the post-transplant status of such patients. A variety of methodologies that address the detection of mutations have been used both in research and clinical diagnostic tests. This study analyzes the genetic variations in cytokines using two methodologies: the traditional allele-specific oligonucleotide (ASO) polymerase chain reaction (PCR) and the newer and more flexible Invader technology. The sensitivity and specificity of the Invader assay for simultaneous investigation of multiple targets makes it a useful tool in such analyses.
Mouse mammary tumor virus (MMTV) is a nonacute transforming retrovirus that causes mammary tumors in susceptible strains of mice. Upon milk-borne transmission, B cells in the gut become infected and subsequently present a virus-encoded superantigen to cognate T cells. These T cells become activated and, in turn, stimulate neighboring lymphocytes, thereby establishing an infection-competent reservoir of lymphoid cells. During puberty and pregnancy, mammary epithelial cells actively divide, and viral transmission occurs from the lymphocytes that migrate to the mammary gland. Thus, MMTV utilizes the immune system to establish infection while simultaneously avoiding immune responses.
IL-10 is overexpressed in human chronic lymphocytic leukemia (CLL), and is an autocrine growth factor involved in the development of malignant B1 clones in NZB mice, a murine model for CLL. Antisense IL-10 oligonucleotide treatment induces apoptosis and cell cycle disruption in these cells both in vitro and in vivo. In addition, NZB IL-10 knock-out mice fail to develop the B-1 clones. Dampening of IL-10 protein production via antisense IL-10 oligonucleotide treatment is correlated with decreased p27/Kip1 protein expression which results in increased cyclin D2, cyclin E and cyclin A associated kinase activity. The action of the antisense oligonucleotides is through alterations in cell cycle regulation, resulting in accelerated cell cycle progression, a G2/M block which culminates in apoptosis induction in the malignant cells. This implies that the role of IL-10 as an autocrine growth factor in malignant B-1 cells lies in its ability to inhibit apoptosis induction through the maintenance of sustainable cell cycle progression in malignant cells.
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