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Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers.

Farzi A, Reichmann F, Meinitzer A, Mayerhofer R, Jain P, Hassan AM, Fröhlich EE, Wagner K, Painsipp E, Rinner B, Holzer P - Brain Behav. Immun. (2014)

Bottom Line: Intraperitoneal injection of FK565 (0.001 or 0.003mg/kg) or MDP (1 or 3mg/kg) 4h before LPS (0.1 or 0.83mg/kg) significantly aggravated and prolonged the LPS-evoked sickness behavior as deduced from a decrease in locomotion, exploration, food intake and temperature.When given alone, FK565 and MDP had only minor effects.Immunohistochemical visualization of c-Fos in the brain revealed that NOD2 synergism with TLR4 resulted in increased activation of cerebral nuclei relevant to sickness.

View Article: PubMed Central - PubMed

Affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria. Electronic address: aitak.farzi@medunigraz.at.

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Effects of MDP (3 mg/kg), FK565 (0.003 mg/kg) and LPS (0.1 mg/kg) on cytokine mRNA expression in the brain 3 h (A–D) and 26 h (E–H) after injection in male mice. Mice were injected i.p. with saline (VEH), MDP, FK565, LPS, MDP + LPS or FK565 + LPS. Expression of IFN-γ (A + E), IL-1β (B + F), IL-6 (C + G), and TNF-α (D + H) was measured 3 h (A–D) or 26 h (E–H) after injection. The values are means + SEM, n = 7–8. (A–D): Post-hoc analysis of significant NOD × LPS interactions in 2-way ANOVA: #p < 0.05, ##p < 0.01, MDP + LPS versus MDP or FK565 + LPS versus FK565. §p < 0.05, §§p < 0.01, MDP + LPS and FK565 + LPS versus LPS. Main factor effects without NOD × LPS interactions: ap < 0.01, LPS versus VEH. bp < 0.05, bbp < 0.01, NLR agonists versus VEH. (E–H): One-way ANOVA: +p < 0.1, ∗p < 0.05, ∗∗p < 0.01, versus VEH or as indicated by the brackets.
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f0030: Effects of MDP (3 mg/kg), FK565 (0.003 mg/kg) and LPS (0.1 mg/kg) on cytokine mRNA expression in the brain 3 h (A–D) and 26 h (E–H) after injection in male mice. Mice were injected i.p. with saline (VEH), MDP, FK565, LPS, MDP + LPS or FK565 + LPS. Expression of IFN-γ (A + E), IL-1β (B + F), IL-6 (C + G), and TNF-α (D + H) was measured 3 h (A–D) or 26 h (E–H) after injection. The values are means + SEM, n = 7–8. (A–D): Post-hoc analysis of significant NOD × LPS interactions in 2-way ANOVA: #p < 0.05, ##p < 0.01, MDP + LPS versus MDP or FK565 + LPS versus FK565. §p < 0.05, §§p < 0.01, MDP + LPS and FK565 + LPS versus LPS. Main factor effects without NOD × LPS interactions: ap < 0.01, LPS versus VEH. bp < 0.05, bbp < 0.01, NLR agonists versus VEH. (E–H): One-way ANOVA: +p < 0.1, ∗p < 0.05, ∗∗p < 0.01, versus VEH or as indicated by the brackets.

Mentions: The expression of cytokine mRNAs in the brain was measured 3 and 26 h after injection of the PRR agonists in order to analyze cytokine expression at the time of predominant sickness and depression-like behavior, respectively (Fig. 6). When cytokine mRNA was assessed 3 h post-treatment, two-way ANOVA revealed a NOD × LPS interaction for the expression of IFN-γ mRNA (F(2,42) = 5.911, p < 0.01) and a trend for IL-6 mRNA expression (F(2,42) = 2.774, p = 0.07). Post-hoc analysis disclosed that while neither MDP (3 mg/kg), FK565 (0.003 mg/kg) nor LPS (0.1 mg/kg) alone increased mRNA expression of IFN-γ or IL-6, combined treatment with MDP + LPS or FK565 + LPS increased IFN-γ and IL-6 mRNA expression compared to LPS or MDP and FK565, respectively (Fig. 6A and C). In contrast, expression of IL-1β mRNA depended on LPS (F(1,42) = 24.984, p < 0.001) and the NOD agonists (F(2,42) = 3.174, p ⩽ 0.05) without a significant interaction (Fig. 6B). Likewise, TNF-α mRNA expression depended on LPS (F(1,42) = 25.735, p < 0.001) and the NOD agonists (F(2,42) = 8.535, p < 0.001) without a significant interaction (Fig. 6D).


Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers.

Farzi A, Reichmann F, Meinitzer A, Mayerhofer R, Jain P, Hassan AM, Fröhlich EE, Wagner K, Painsipp E, Rinner B, Holzer P - Brain Behav. Immun. (2014)

Effects of MDP (3 mg/kg), FK565 (0.003 mg/kg) and LPS (0.1 mg/kg) on cytokine mRNA expression in the brain 3 h (A–D) and 26 h (E–H) after injection in male mice. Mice were injected i.p. with saline (VEH), MDP, FK565, LPS, MDP + LPS or FK565 + LPS. Expression of IFN-γ (A + E), IL-1β (B + F), IL-6 (C + G), and TNF-α (D + H) was measured 3 h (A–D) or 26 h (E–H) after injection. The values are means + SEM, n = 7–8. (A–D): Post-hoc analysis of significant NOD × LPS interactions in 2-way ANOVA: #p < 0.05, ##p < 0.01, MDP + LPS versus MDP or FK565 + LPS versus FK565. §p < 0.05, §§p < 0.01, MDP + LPS and FK565 + LPS versus LPS. Main factor effects without NOD × LPS interactions: ap < 0.01, LPS versus VEH. bp < 0.05, bbp < 0.01, NLR agonists versus VEH. (E–H): One-way ANOVA: +p < 0.1, ∗p < 0.05, ∗∗p < 0.01, versus VEH or as indicated by the brackets.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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f0030: Effects of MDP (3 mg/kg), FK565 (0.003 mg/kg) and LPS (0.1 mg/kg) on cytokine mRNA expression in the brain 3 h (A–D) and 26 h (E–H) after injection in male mice. Mice were injected i.p. with saline (VEH), MDP, FK565, LPS, MDP + LPS or FK565 + LPS. Expression of IFN-γ (A + E), IL-1β (B + F), IL-6 (C + G), and TNF-α (D + H) was measured 3 h (A–D) or 26 h (E–H) after injection. The values are means + SEM, n = 7–8. (A–D): Post-hoc analysis of significant NOD × LPS interactions in 2-way ANOVA: #p < 0.05, ##p < 0.01, MDP + LPS versus MDP or FK565 + LPS versus FK565. §p < 0.05, §§p < 0.01, MDP + LPS and FK565 + LPS versus LPS. Main factor effects without NOD × LPS interactions: ap < 0.01, LPS versus VEH. bp < 0.05, bbp < 0.01, NLR agonists versus VEH. (E–H): One-way ANOVA: +p < 0.1, ∗p < 0.05, ∗∗p < 0.01, versus VEH or as indicated by the brackets.
Mentions: The expression of cytokine mRNAs in the brain was measured 3 and 26 h after injection of the PRR agonists in order to analyze cytokine expression at the time of predominant sickness and depression-like behavior, respectively (Fig. 6). When cytokine mRNA was assessed 3 h post-treatment, two-way ANOVA revealed a NOD × LPS interaction for the expression of IFN-γ mRNA (F(2,42) = 5.911, p < 0.01) and a trend for IL-6 mRNA expression (F(2,42) = 2.774, p = 0.07). Post-hoc analysis disclosed that while neither MDP (3 mg/kg), FK565 (0.003 mg/kg) nor LPS (0.1 mg/kg) alone increased mRNA expression of IFN-γ or IL-6, combined treatment with MDP + LPS or FK565 + LPS increased IFN-γ and IL-6 mRNA expression compared to LPS or MDP and FK565, respectively (Fig. 6A and C). In contrast, expression of IL-1β mRNA depended on LPS (F(1,42) = 24.984, p < 0.001) and the NOD agonists (F(2,42) = 3.174, p ⩽ 0.05) without a significant interaction (Fig. 6B). Likewise, TNF-α mRNA expression depended on LPS (F(1,42) = 25.735, p < 0.001) and the NOD agonists (F(2,42) = 8.535, p < 0.001) without a significant interaction (Fig. 6D).

Bottom Line: Intraperitoneal injection of FK565 (0.001 or 0.003mg/kg) or MDP (1 or 3mg/kg) 4h before LPS (0.1 or 0.83mg/kg) significantly aggravated and prolonged the LPS-evoked sickness behavior as deduced from a decrease in locomotion, exploration, food intake and temperature.When given alone, FK565 and MDP had only minor effects.Immunohistochemical visualization of c-Fos in the brain revealed that NOD2 synergism with TLR4 resulted in increased activation of cerebral nuclei relevant to sickness.

View Article: PubMed Central - PubMed

Affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria. Electronic address: aitak.farzi@medunigraz.at.

Show MeSH
Related in: MedlinePlus