Cytotoxicity of Human p I 7 Interleukin-1 for Pancreatic Islets of Langerhans

Abstract

Activated mononuclear cells appear to be important effector cells in autoimmune beta cell destruction leading to insulin-dependent (type 1) diabetes mellitus. Conditioned medium from activated mononuclear cells (from human blood) is cytotoxic to isolated rat and human islets of Langerhans. This cytotoxic activity was eliminated from crude cytokine preparations by adsorption with immobilized, purified antibody to interleukin-1 (IL-1). The islet-inhibitory activity and the IL-1 activity (determined by its comitogenic effect on thymocytes) were recovered by acid wash. Purified natural IL-1 and recombinant IL-1 derived from the predominant pI 7 form of human IL-1, consistently inhibited the insulin response. The pI 6 and pI 5 forms of natural IL-1 were ineffective. Natural and recombinant IL-1 exhibited similar dose responses in their islet-inhibitory effect and their thymocyte-stimulatory activity. Concentrations of IL-1 that inhibited islet activity were in the picomolar range. Hence, monocyte-derived pI 7 IL-1 may contribute to islet cell damage and therefore to the development of insulin-dependent diabetes mellitus.

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

“…Values after 3 days exposure to IL-1β (50 U/ml) and IFN-γ (1,000 U/ml) were determined by ELISA and with Griess reagent protocol respectively, and are expressed as means±SEM from three to four independent experiments. One superscript symbol p≤0.05, two superscript symbols p≤0.01; three superscript symbols p≤0.001, four superscript symbols p≤0.0001: ( †) compared with control C57BL/6 islets (under similar conditions); (*) compared with control C57BL/6 islets (no cytokines added); ( ‡) compared with Irf-1 −/− islets (no cytokines added) only minor effects on cell viability [6,38]; they also show that blocking IL-1β action with IL-1Ra can prevent the deleterious effects [24,34,[39][40][41][42]. Although this was confirmed in our study, we observed abnormal glucosestimulated insulin release from Irf-1 −/− islets under basal conditions that could not be corrected by IL-1Ra, indicating an independent defect in beta cell secretory machinery of Irf-1 −/− islets.…”

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

“…Amyloid deposits are comprised primarily of islet amyloid polypeptide (IAPP), 5 a 37-amino acid peptide that is co-secreted with insulin by beta cells. Recent evidence suggests that IAPP aggregates trigger islet secretion of IL-1, which acts alone or in combination with other pro-inflammatory cytokines to impair beta cell insulin secretion (5,6). Human but not non-amyloidogenic rodent IAPP induces IL-1␤ synthesis in bone marrow-derived and intra-islet macrophages (7,8).…”

Cytokines and autoimmunity

“…cells and thyroid epithelial cells are susceptible to cytokine-mediated damage. In particular, the deleterious eflects of IL-1^ on pancreatic fi islet cells in vitro have been clearly established [61][62][63][64][65]. It has also been demonstrated that the exposure of fi islet cells to this cytokine leads to a potent inhibition of cell function.…”

“…The eflect of IL-1 on fi islet cells in culture was found to be both time-and dose-dependent. Thus, acute exposure to IL-l/3 produced a stimulation of fi islet cell function with increased insulin production, whilst long-term exposure suppressed insulin production and release, ultimately leading to fi islet cell death [61,65]. The eflects described appear to be mediated by the binding of IL-1 to specific receptors [66] which has been demonstrated on both fi islet cells and thyrocytes [67,68], and seems to involve the generation of oxygen free radicals [69,70].…”