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      Anti-Inflammatory Activity of Citric Acid-Treated Wheat Germ Extract in Lipopolysaccharide-Stimulated Macrophages

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          Abstract

          Until recently, fermentation was the only processing used to improve the functionality of wheat germ. The release of 2,6-dimethoxy-1,4-benzoquinone (DMBQ) from hydroquinone glycosides during the fermentation process is considered a marker of quality control. Here, we treated wheat germ extract with citric acid (CWG) to release DMBQ and examined the anti-inflammatory activity of this extract using a lipopolysaccharide-activated macrophage model. Treatment of wheat germ with citric acid resulted in detectable release of DMBQ but reduced total phenolic and total flavonoid contents compared with untreated wheat germ extract (UWG). CWG inhibited secretion of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, and IL-12 and the synthesis of cyclooxygenase-2, while UWG only decreased IL-12 production. CWG and UWG induced high levels of anti-inflammatory IL-10 and heme oxygenase-1. CWG specifically inhibited phosphorylation of NF-κB p65 and p38 kinase at 15 min after LPS stimulation. Our study showed that citric acid treatment enhanced the anti-inflammatory activity of wheat germ extract.

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          Most cited references31

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          M-1/M-2 macrophages and the Th1/Th2 paradigm.

          Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-gamma or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-beta1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-gamma production, while BALB/c SCID macrophages increase TGF-beta production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.
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            Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice.

            The mechanisms underlying the action of the potent anti-inflammatory interleukin-10 (IL-10) are poorly understood. Here we show that, in murine macrophages, IL-10 induces expression of heme oxygenase-1 (HO-1), a stress-inducible protein with potential anti-inflammatory effect, via a p38 mitogen-activated protein kinase-dependent pathway. Inhibition of HO-1 protein synthesis or activity significantly reversed the inhibitory effect of IL-10 on production of tumor necrosis factor-alpha induced by lipopolysaccharide (LPS). Additional experiments revealed the involvement of carbon monoxide, one of the products of HO-1-mediated heme degradation, in the anti-inflammatory effect of IL-10 in vitro. Induction of HO-1 by IL-10 was also evident in vivo. IL-10-mediated protection against LPS-induced septic shock in mice was significantly attenuated by cotreatment with the HO inhibitor, zinc protoporphyrin. The identification of HO-1 as a downstream effector of IL-10 provides new possibilities for improved therapeutic approaches for treating inflammatory diseases.
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              Macrophage activation by endogenous danger signals.

              Macrophages are cells that function as a first line of defence against invading microorganisms. One of the hallmarks of macrophages is their ability to become activated in response to exogenous 'danger signals'. Most microbes have molecular patterns (PAMPS) that are recognized by macrophages and trigger this activation response. There are many aspects of the activation response to PAMPS that are recapitulated when macrophages encounter endogenous danger signals. In response to damaged or stressed self, macrophages undergo physiological changes that include the initiation of signal transduction cascades from germline-encoded receptors, resulting in the elaboration of chemokines, cytokines and toxic mediators. This response to endogenous mediators can enhance inflammation, and thereby contribute to autoimmune pathologies. Often the overall inflammatory response is the result of cooperative activation signals from both exogenous and endogenous signals. Macrophage activation plays a critical role, not only in the initiation of the inflammatory response but also in the resolution of this response. The clearance of granulocytes and the elaboration of anti-inflammatory mediators by macrophages contribute to the dissolution of the inflammatory response. Thus, macrophages are a key player in the initiation, propagation and resolution of inflammation. This review summarizes our understanding of the role of macrophages in inflammation. We pay particular attention to the endogenous danger signals that macrophages may encounter and the responses that these signals induce. The molecular mechanisms responsible for these responses and the diseases that result from inappropriately controlled macrophage activation are also examined. 2007 Pathological Society of Great Britain and Ireland
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                10 July 2017
                July 2017
                : 9
                : 7
                : 730
                Affiliations
                [1 ]Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17104, Korea; jhy9592@ 123456naver.com
                [2 ]Sajo DongA One Co., Ltd., Dangjin 31703, Korea; knownet@ 123456sajo.co.kr (Y.-S.C.); macmen@ 123456sajo.co.kr (J.-K.L.)
                [3 ]Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; franchisjun@ 123456khu.ac.kr
                [4 ]Department of Food Science and Biotechnology, Kyung Hee University, Yongin 17104, Korea; kimw@ 123456khu.ac.kr
                Author notes
                [* ]Correspondence: shehee@ 123456khu.ac.kr ; Tel.: +82-31-201-3854
                Article
                nutrients-09-00730
                10.3390/nu9070730
                5537844
                28698513
                06f6432b-2afd-4b7b-b4ea-5d91578e66b9
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 May 2017
                : 07 July 2017
                Categories
                Article

                Nutrition & Dietetics
                wheat germ,citric acid,inflammation,macrophage
                Nutrition & Dietetics
                wheat germ, citric acid, inflammation, macrophage

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