Macrophages and Inflammatory Mediators in Chemical Toxicity: A Battle of Forces

Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854.
Chemical Research in Toxicology (Impact Factor: 3.53). 08/2009; 22(8):1376-85. DOI: 10.1021/tx900086v
Source: PubMed


Macrophages function as control switches of the immune system, providing a balance between pro- and anti-inflammatory responses. To accomplish this, they develop into different subsets: classically (M1) or alternatively (M2) activated macrophages. Whereas M1 macrophages display a cytotoxic, proinflammatory phenotype, much like the soldiers of The Dark Side of The Force in the Star Wars movies, M2 macrophages, like Jedi fighters, suppress immune and inflammatory responses and participate in wound repair and angiogenesis. Critical to the actions of these divergent or polarized macrophage subpopulations is the regulated release of inflammatory mediators. When properly controlled, M1 macrophages effectively destroy invading pathogens, tumor cells, and foreign materials. However, when M1 activation becomes excessive or uncontrolled, these cells can succumb to The Dark Side, releasing copious amounts of cytotoxic mediators that contribute to disease pathogenesis. The activity of M1 macrophages is countered by The Force of alternatively activated M2 macrophages, which release anti-inflammatory cytokines, growth factors, and mediators involved in extracellular matrix turnover and tissue repair. It is the balance in the production of mediators by these two macrophage subpopulations that ultimately determines the outcome of the tissue response to chemical toxicants.

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    • "The liver injury develops within three to five hours following exposure of APAP toxic dose and reaches the peak at 12 hours [4]. Cell injury elicits inflammatory reaction in the liver [5]. 11í µí»½-Hydroxysteroid dehydrogenase type 1 (11í µí»½-HSD type 1) enzyme is a native enzyme in liver and interconverts inactive glucocorticoids (cortisone) to active cortisol which has anti-inflammatory action [6]. "
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    ABSTRACT: Hepatic injury induces inflammatory process and cell necrosis. Plantago major is traditionally used for various diseases. This study aimed to determine the anti-inflammatory property of P. major leaf extracts on inflammatory reaction following acetaminophen (APAP) hepatotoxicity. Thirty male Sprague-Dawley rats were divided into 5 groups, namely, normal control (C), APAP, aqueous (APAP + AQ), methanol (APAP + MT), and ethanol (APAP + ET) extract treated groups. All APAP groups received oral APAP (2 g/kg) at day 0. Then, 1000 mg/kg dose of P. major extracts was given for six days. The levels of liver transaminases were measured at day 1 and day 7 after APAP induction. At day 7, the blood and liver tissue were collected to determine plasma cytokines and tissue 11 β -HSD type 1 enzyme. The in vitro anti-inflammatory activities of methanol, ethanol, and aqueous extracts were 26.74 ± 1.6%, 21.69 ± 2.81%, and 12.23 ± 3.15%, respectively. The ALT and AST levels were significantly higher in the APAP groups at day 1 whereas the enzyme levels of all groups showed no significant difference at day 7. The extracts treatment significantly reduced the proinflammatory cytokine levels and significantly increased the 11 β -HSD type 1 enzyme activity ( p < 0.05 ). In conclusion, the P. major extracts attenuate the inflammatory reaction following APAP-induced liver injury.
    Evidence-based Complementary and Alternative Medicine 08/2015; 2015(9):1-7. DOI:10.1155/2015/347861 · 1.88 Impact Factor
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    • "In contrast, M2 macrophages release anti-inflammatory mediators, down-regulating M1 responses and promoting tissue remodeling and angiogenesis. As the changes in the M1/M2 phenotypic balance can exacerbate inflammation systems and cause DILI (Laskin, 2009; Holt et al., 2008), we examined mRNA expression associated with macrophage phenotypes, M1 markers (iNOS), and M2 markers (Arg-1, Fizz1, and Ym1) (Fig. 6). APAP decreased LPSinduced iNOS and Arg-1 expression, and troglitazone also caused suppression in LPS-induced iNOS, Arg-1, Fizz1, and Ym1 expression, as shown Fig. 6. "
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    ABSTRACT: In recent years, attention has been paid to innate immune systems as mechanisms to initiate or promote drug-induced liver injury (DILI). Kupffer cells are hepatic resident macrophages and might be involved in the pathogenesis of DILI by release of pro- and anti-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and/or nitric oxides. The purpose of this study was to investigate alterations in mediator levels induced by hepatotoxic compounds in isolated Kupffer cells and discuss the relation between balance of each cytokine or chemokine and potential of innate immune-mediated DILI. Primary cultured rat Kupffer cells were treated with hepatotoxic (acetaminophen, troglitazone, trovafloxacin) or non-hepatotoxic (pioglitazone, levofloxacin) compounds with or without lipopolysaccharide (LPS). After 24 hr treatment, cell supernatants were collected and various levels of mediators released by Kupffer cells were examined. Although hepatotoxicants had no effect on the LPS-induced tumor necrosis factor-alpha (TNF-α) secretion, they enhanced the release of pro-inflammatory cytokine interleukin-1 beta (IL-1β) and suppressed the anti-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) induced by LPS. These cytokine shifts were not associated with switching the phenotypes of M1 and M2 macrophages in Kupffer cells. In conclusion, the present study suggested that the levels of some specific cytokines are affected by DILI-related drugs with LPS stimulation, and imbalance between pro- and anti-inflammatory cytokines, induced by the up-regulation of IL-1β and the down-regulation of IL-6 or IL-10, plays a key role in innate immune-mediated DILI.
    The Journal of Toxicological Sciences 05/2015; 40(3):389-404. DOI:10.2131/jts.40.389 · 1.29 Impact Factor
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    • "Recruited hepatic macrophages play an important role in liver repair after liver injury [29]. Immunostaining revealed that the number of F4/80-positive cells in WT livers and VEGFR1 TK-/- livers reduced compared with sham-controls, reaching a nadir at 6 h and then increasing gradually thereafter (n = 5–6 per group) (Fig. 3A, Fig. S4). "
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    PLoS ONE 08/2014; 9(8):e105533. DOI:10.1371/journal.pone.0105533 · 3.23 Impact Factor
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