Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma

Abstract

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.

Mouse Models of Chronic Lymphocytic Leukemia

“…In this regard, Ramachandra and coworkers (Ramachandra et al, 1996) demonstrated that high interleukin (IL)-10 levels in NZB mice were correlated with B-1 cell transformation. In agreement with a role for IL-10 in CLL development in this mouse model, IL-10 depletion achieved either by targeting deletion of the IL-10 gene (Czarneski et al, 2004) or by in vivo administration of antisense IL-10 (Parker et al, 2000;Peng et al, 1995) delayed, and even prevented, CLL development. IL-5 is another member of the IL family that seems to play an important role as a switch for SLE or CLL development.…”

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

“…Treatment with z-VRPRfmk for 36 hours and more also led to a predominant reduction in the transcription and expression of IL-10 ( Fig. 3D), which can promote the growth of activated B cells and B-cell lymphomas (20)(21)(22). The observed reduction of IL-6 and IL-10 cytokine levels in VRPR-fmk treated ABC DLBCL lines correlated with a decrease in the expression of these genes in two ABC DLBCL lines treated with the MALT1 inhibitor (Fig.…”

Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma

“…21 Mouse B-cell lymphomas that arise spontaneously in the New Zealand Black strain produce IL-10, and IL-10 is required for their generation. 22 IL-6 and IL-10 are secreted by malignant cells purified from some patients with non-Hodgkin lymphoma (NHL), and this phenotype correlates with circulating levels of the corresponding cytokines in serum. 23 Binding of IL-6 and IL-10 to their surface receptors activates JAK family kinases, initiating several cascades of intracellular signaling events.…”