Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans.

Abstract

SllmmAryTransgenic expression of interleukin 10 (IL-10) in the islets of Langerhans leads to a pronounced pancreatic inflammation, without inflammation of the islets of Langerhans and without diabetes. A scattered infiltration of macrophages (Mtk) precedes localized accumulations of CD4 + and CD8 + T lymphocytes, B lymphocytes, and Mtk. This recruitment of inflammatory cells to the pancreas is somewhat surprising, since the biological activities of IL-10 in vitro indicate that IL-10 is a powerful immunosuppressive cytokine. Since endothelial cells play a major role in leukocyte extravasation, we examined if vascular changes and extralymphoid induction of peripheral and mucosal type vascular addressins contributed to IL-lO-induced homing of mononudear cells to the pancreas. The endothelium lining small vessds was highly activated in areas of inflammation, as the endothelial cells became cuboidal, and exhibited increased expression of major histocompatibility complex dass II (Ia), intercellular adhesion molecule 1, and *con WiUebrand Factor. Furthermore, induction of vascular addressins simultaneously with accumulation of mononuclear cells around islets and vessels indicated that the endothelial cells take on the phenotype of differentiated endothelium specialized for leukocyte extravasation. In conclusion, pancreatic inflammation and vascular changes are prominent in IL-IO transgenic mice. We hypothesize that IL-IO, in addition to its immuno-inhibitory properties, is a potent recruitment signal for leukocyte migration in vivo. These effects are relevant for in vivo therapeutic applications of IL-IO.

Different Therapeutic Outcomes in Experimental Allergic Encephalomyelitis Dependant Upon the Mode of Delivery of IL-10: A Comparison of the Effects of Protein, Adenoviral or Retroviral IL-10 Delivery into the Central Nervous System

“…There was a significant increase in frequency of CD8 ϩ T cells and B cells in IL-10.tsF-treated mice. This supports previous work, which has shown that IL-10 can promote the growth of activated CD8 ϩ cells (38,39) and that increased pancreatic infiltration of CD4 ϩ , CD8 ϩ T and B cells were observed in an IL-10 transgenic model in NOD mice (40,41). In contrast to both the transgenic NOD study and the results we present here, transgenic mice constitutively producing human IL-10 (400 -700 pg/ml in serum) were protected from the induction of EAE and failed to show histological evidence of CNS infiltration (42).…”

IL-10 expression by CT26 colon carcinoma cells inhibits their malignant phenotype and induces a T cell-mediated tumor rejection in the context of a systemic Th2 response

“…In particular, the identity of the cells which may prime CD4 + T cells given the fact that CT26 do not express MHC class II and IL-10 was shown to prevent macrophage and dendritic cell accumulation in the vicinity of certain tumor models. 17, 27 The present data and previous evidence showing that IL-10 may act as a potent leukocyte chemoattractant in vivo 28 and in vitro 29 suggest that IL-10 may inhibit tumor cell growth by accelerating leukocyte recruitment to the site of injection. It can be hypothesized that once T cells reach the tumor target, they can be activated in situ to eliminate the tumor cells.…”

IL-10-Conditioned Dendritic Cells, Decommissioned for Recruitment of Adaptive Immunity, Elicit Innate Inflammatory Gene Products in Response to Danger Signals

“…These data contrast with previous reports of the anti-inflammatory effect of IL-10 in in vivo models (37,53,54), and probably reflect the critical importance of context in cytokine behavior. Indeed, the effects of IL-10 in vivo, and on individual cell types, are not always anti-inflammatory (55)(56)(57). Down-modulation of the IL-1R2 decoy receptor in response to IL-10 is suggestive of priming for IL-1 responsiveness, while the general increase in degrading lysosomal activity, in association with LPS-induced expression of membrane bound and soluble pattern recognition molecules, is indicative of enhanced phagocytic bacterial clearance (Table I).…”