Abstract
Proinflammation can predispose the body to autoimmunity and cancer. We have reported that iPLA2β−/− mice are susceptible to autoimmune hepatitis and colitis. Here we determined whether cytokine release by immune cells could be affected by iPLA2β deficiency alone or combined with CD95/FasL-antibody treatment in vivo. We also determined whether cancer risk could be increased in aged mutant mice. Immune cells were isolated from 3-month old male WT and iPLA2β−/− mice, and some were injected with anti-CD95/FasL antibody for 6 h. Kupffer cells (KC) or splenocytes and liver lymphocytes were stimulated in vitro by lipopolysaccharide or concanavalinA, respectively. Whole-body iPLA2β deficiency caused increased apoptosis in liver, spleen, and mesenteric lymph node (MLN). KC from mutant mice showed suppressed release of TNFα and IL-6, while their splenocytes secreted increased levels of IFNγ and IL-17a. Upon CD95/FasL activation, the mutant KC in turn showed exaggerated cytokine release, this was accompanied by an increased release of IFNγ and IL-17a by liver lymphocytes. Aged iPLA2β−/− mice did not show follicular MLN lymphoma commonly seen in aged C57/BL6 mice. Thus, iPLA2β deficiency renders M1- and Th1/Th17-proinflammation potentially leading to a reduction in age-related MLN lymphoma during aging.
Highlights
Cancer development has been linked to environmental factors such as tobacco, obesity and infections which affect cancer incidence by 30%, 14%–20%, and 18%, respectively [1]
As CD95/FasL is capable of inducing proinflammatory cytokines [26], we further studied whether treatment of iPLA2β{ ́ mice with anti-CD95/FasL antibody would cause exaggerated cytokine release by immune cells
Regarding Jo2 treatment in vivo, macrophages and Kupffer cells (KC) appeared to be the first line of cells which were strongly sensitized by iPLA2β deficiency, and these primed cells may have in turn elicited sensitized effects onto liver lymphocytes with a lesser extent in response pattern
Summary
Cancer development has been linked to environmental factors such as tobacco, obesity and infections which affect cancer incidence by 30%, 14%–20%, and 18%, respectively [1]. IPLA2β deficiency at the whole body level may elicit systemic effects associated with chronic inflammation in several tissues, and essentially leading to injury such as seen in the bone and brain of aged mutant mice [10,11]. It has been shown that iPLA2β mediates apoptotic cell clearance through the generation of lysophosphatidylcholine (LPC) [15], and the enzyme itself has been shown to regulate the speed and directionality of monocytes during chemotaxis [16] This defect in apoptotic cell clearance might explain the observed susceptibility of iPLA2β{ ́ mice towards stress-induced injury. We determined whether iPLA2β deficiency could affect lymphoma incidence of a cancer prone immune organ—mesenteric lymph node (MLN)
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