Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice☆

Abstract

Consumption of the trichothecene mycotoxin deoxynivalenol (DON) induces interleukin-6 (IL-6)-dependent IgA nephropathy (IgAN) in mice. This effect can be prevented by feeding long chain n-3 polyunsaturated fatty acids (PUFAs) found in fish oil. The purpose of this study was to identify the signal transduction pathways by which DON upregulates IL-6 in the peritoneal macrophage and how consumption of fish oil enriched with the n-3 PUFA, docosahexaenoic acid (DHA), suppresses these processes. Incubation with DON induced IL-6 expression in naïve macrophages maximally at 3 h. Knockdown of the transcription factor cAMP response element-binding protein (CREB) or pharmacologic inhibition of the CREB kinases, Akt1/2, MSK1 and RSK1, downregulated this expression. Inhibition of double-stranded RNA-activated protein kinase (PKR) suppressed not only IL-6 expression but also phosphorylation of CREB and its upstream kinases, Akt1, MSK1 and RSK1. Phosphorylations of PKR, CREB kinases and CREB were markedly impaired in peritoneal macrophages isolated from mice that consumed DHA-enriched fish oil for 6 to 8 wk. DHA’s effects were not explainable by increased activity of protein phosphatase 1 and 2A since both were suppressed in mice consuming the DHA diet. Although cells cultured directly with DHA expressed less IL-6 compared to cells cultured with arachidonic acid (AA), neither fatty acid treatment affected DON-induced protein phosphorylation. Furthermore, DHA and AA similarly inhibited cell-free protein kinase activity. These data suggest that DON-induced IL-6 expression is CREB-mediated and PKR-dependent and that requisite kinase activities for these pathways were suppressed in macrophages from mice fed DHA for an extended period.

Dietary Fish Oil Alters T Lymphocyte Cell Populations and Exacerbates Disease in a Mouse Model of Inflammatory Colitis

“…The composition was based on the AIN-93G formulation of Reeves (30) and modified as described previously (31). Control corn oil (CO) diets contained 70 g/kg CO (Dyets); control safflower oil (SF) diets contained 10 g/kg CO and 60 g/kg high oleic acid SF (Spectrum Naturals).…”

Prospects and Perspectives on IgA Nephropathy from Animal Models

“…In the same model, other investigators demonstrated the beneficial effects of fish oil [42,43], rich in ω-3 PUFA that shunt eicosanoid metabolism towards less phlogogenic isoforms. Collaterally, similar effects of eicosapentaneoic or docosahexaenoic acids (also ω-3 PUFAs) have proven salutary in the mouse model of IgANinduced by vomitoxin [139,140,142]. Although genetic ablation or pharmacologic inhibition of cyclooxygenase 2 further exaggerated IgA production in this model, reduced activity of this enzyme did not influence disease parameters [143].…”

“…Diminished IL-6 production attendant upon ω-3 PUFA dietary supplementation was associated with marked reduction of the signs of IgAN in this model [139,140]. Suspensions of mouse peritoneal macrophages in vitro increase IL-6 expression in response to addition of mycotoxin through the effect of RNA-activated protein kinase phosphorylation; these kinases then act upon the cAMP response element-binding protein (CREB) [142]. In each of these systems, overproduction of IgA and glomerular deposition of IgA are roughly correlated, and it is difficult to determine whether the effects of IL-6 reside principally with increased IgA production, with the glomerular response to IgA deposition, or from synergy between these two possibilities.…”

“…The most extensive experimental therapeutics relate to altering eicosanoids by use of ω-3 polyunsaturated fatty acids [41,43,139,140,142] and diminution of oxidative stress owing to these agents or, more pointedly, to use of vitamin E [41][42][43], all with favorable results to at least some extent. Antagonists of cytokines [46], growth factors [146] or chemokines [155] have also ameliorated varying signs of experimental IgAN, as have treatment with probiotics [37] or traditional herbal remedies with unknown mechanisms [36,44,45,60].…”

Deoxynivalenol-induced cytokines and related genes in concanavalin A-stimulated primary chicken splenic lymphocytes

“…In contrast, others have shown increased IL-6 production in mice (Azcona-Olivera et al, 1995b;Dong et al, 1994;Zhou et al, 1997;Kaiser et al, 2004;Pestka and Amuzie, 2008;Wan et al, 2013;Chung et al, 2003a;Shi and Pestka, 2006;Moon and Pestka, 2003b;Islam and Pestka, 2006). Interestingly, another set of studies in pigs and mice has demonstrated the obvious induction of IL-6 mRNA expression by DON after 2-4 h of treatment time, and the decrease thereafter (Azcona-Olivera et al, 1995b;Kinser et al, 2005;Doll et al, 2009b;Shi and Pestka, 2009). IFN-c levels were also elevated, similar with previous studies on humans and mice (Azcona-Olivera et al, 1995a;Zhou et al, 1997;Meky et al, 2001).…”