Fever, sickness behavior, and expression of inflammatory genes in the hypothalamus after systemic and localized subcutaneous stimulation of rats with the toll-like receptor 7 agonist imiquimod

Damm, Jelena; Wiegand, Florian; Harden, Lois M.; Gerstberger, Rüdiger; Rummel, Christoph; Roth, Joachim

doi:10.1016/j.neuroscience.2011.11.013

Cited by 51 publications

(44 citation statements)

References 72 publications

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“…Similarly, only a modest sickness response was evidenced as a slight decrease in food and water intake but no change in overall LMA of rats (Damm et al, 2012). I have confirmed this and found a modest sickness response to imiquimod with mice (R.H.M., unpublished observations).…”

Section: Tlr3 Tlr7 Tlr8 and Tlr9: Nucleic Acidsmentioning

confidence: 55%

Immune–neural connections: how the immune system’s response to infectious agents influences behavior

McCusker

Kelley

2013

Journal of Experimental Biology

358

259

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Sickness and depressionOver the past 30years, it has become clear that the immune system plays a critical role in animal behavior. This role is tightly linked to the obvious role that immune cell activation plays in the clearance of pathogenic organisms. Systemic or central infections elicit a group of symptoms that are necessary for the organism to conserve resources, reorganize priorities and limit the spread of the infection to other members of the community. This sickness behavior is a motivational state that is common to most pathogeninduced infections ranging from viruses to multicellular parasites, but, because of its ubiquitous nature, is frequently accepted as an unavoidable and non-specific consequence of infection. However, considering the broad spectrum of symptoms -fever, nausea, decreased appetite, malaise, fatigue and achiness -it seems clear that a highly organized, although not pathogen-specific, response is being manifested to aid in the fight against infection (Dantzer, 2001;Ericsson et al., 1995).We are all familiar with the human symptoms of sickness but, to investigate changes in behavior associated with sickness, it is critical to have reliable animal measurements that relate to changes in the affective state. Using preclinical animal models, sickness behavior is best evaluated when the test involves a means to assess motivation. Sickness behavior is frequently assessed as social exploration/investigation (in rodent models, this response is frequently reported as a decrease in time actively seeking interaction with a novel animal as a result of diminished motivation for social exploration or neophobia). Social exploration is a naturalistic behavior and all animals have a strong motivation, whether driven by curiosity or sexual desire. With this strong motivational stimulus, infections cause a strong differential between time of exploration of healthy and sick animals, with less time of exploration being observed with sick animals. Another simpler but effective model is exploration of the environment [often referred to as locomotor activity (LMA), representing some level of physical movement in a novel environment such as rearing, quadrant entry, line crossings or total distance traveled; all of which are highly correlated]. LMA is best conducted in a novel environment, as the motivation to explore is stronger in this

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Section: Tlr3 Tlr7 Tlr8 and Tlr9: Nucleic Acidsmentioning

confidence: 55%

Immune–neural connections: how the immune system’s response to infectious agents influences behavior

McCusker

Kelley

2013

Journal of Experimental Biology

358

259

View full text Add to dashboard Cite

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“…Fever is one of the most important signs of immune system activation, with an adaptive function that modifies the organism's internal environment to become unfavorable to the survival of pathogens [27,28,29,30]. After exposure to pathogens, a series of proinﬂammatory cytokines is produced by immune-competent cells, and various transcription factors are activated within the fever-controlling region of the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Temporal Analysis of Lipopolysaccharide-Induced Sickness Behavior in Virgin and Lactating Female Rats

Nascimento

Bernardi

Pecorari

et al. 2013

Neuroimmunomodulation

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Objectives: Lipopolysaccharide (LPS), an endotoxin that originates from the cell wall of Gram-negative bacteria, activates the immune system to release proinflammatory cytokines and to induce sickness behavior. The present study sought to characterize the time-dependent effects of LPS on fever, body weight, and food and water consumption in female virgin and lactating rats exposed to an LPS dose previously reported to induce sickness behavior in pregnant female rats. Methods: Virgin female Wistar rats in the estrous phase and lactating female Wistar rats on the third day of lactation received 100 µg/kg LPS or saline solution. Tympanic temperature, body weight, and food and water consumption were assessed 0, 2, 24, 48, 72, 96, and 120 h after treatment. Results: In lactating female rats, tympanic temperature was attenuated compared with virgin females. Food consumption and body weight gain in both groups decreased, but lactating rats consumed more food than virgin rats. Water consumption increased at different time points. Conclusion: LPS exposure induced several signs of sickness behavior, including decreases in food consumption and body weight gain, and induced adipsia in both virgin and lactating female rats. Because the time course and profile of fever varied between lactating and nonlactating animals, these responses appeared to depend on the physiological state of female animals.

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“…This interpretation is backed up by the literature on "endogenous pyrogens" (Dinarello, 1999) and on imiquimod (Damm et al, 2012).…”

Section: Discussionmentioning

confidence: 96%

“…The first example is a low-molecular weight compound "imiquimod", a Tlr7 agonist, already on the market for treatment of skin viral infection (Hemmi et al, 2002). Subcutaneous injection of imiquimod was reported to induce fever, sickness behavior and induction of ISG in rats (Damm et al, 2012). The second example is a new polyfluoromethylated compound, 8-(1, 3,4-oxadiazol-2-yl)-2, 4-bis (trifluoromethyl) imidazo [1, 2-a] [1, 8] naphthyridine (RO4948191) which was reported to be an orally available low molecular weight interferon receptor agonist.…”

Section: Discussionmentioning

confidence: 99%

Oral administration of pentachlorophenol induces interferon signaling mRNAs in C57BL/6 male mouse liver

Kanno¹,

Aisaki²,

Igarashi³

et al. 2013

J. Toxicol. Sci.

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-Pentachlorophenol (PCP) was monitored for transcriptome responses in adult mouse liver at 2, 4, 8 and 24 hr after a single oral administration at four dose levels, 0, 10, 30 and 100 mg/kg. The expression data obtained using Affymetrix GeneChip MOE430 2.0 were absolutized by the Percellome method and expressed as three dimensional (3D) surface graphs with axes of time, dose and copy numbers of mRNA per cell. We developed the programs RSort, for comprehensive screening of the 3D surface data and PercellomeExploror for cross-referencing and confirmed the significant responses by visual inspection. In the first 8 hr, approximately 100 probe sets (PSs) related to PXR/SXR and Cyp2a4 and other metabolic enzymes were induced whereas Fos and JunB were suppressed. At 24 hr, about 1,200 PSs were strongly induced. We cross-referenced the Percellome database consisting of 111 chemicals on the liver transcriptome and found that about half of the PSs belonged to the metabolic pathways including Nrf2-mediated oxidative stress response networks shared with some of the 111 chemicals. The other half of the induced genes were interferon signaling network genes (ISG) and their induction was unique to PCP. Toll like receptors and other pattern recognition receptors, interferon regulatory factors and interferon alpha itself were included but inflammatory cytokines were not induced. In summary, these data indicated that functional symptoms of PCP treatment, such as hyperthermia and profuse sweating might be mediated by the ISG rather than the previously documented mitochondrial uncoupling mechanism. PCP might become a hint for developing low molecular weight orally available interferon mimetic drugs following imiquimod and RO4948191 as agonists of toll-like receptor and interferon receptor.

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Fever, sickness behavior, and expression of inflammatory genes in the hypothalamus after systemic and localized subcutaneous stimulation of rats with the toll-like receptor 7 agonist imiquimod

Cited by 51 publications

References 72 publications

Immune–neural connections: how the immune system’s response to infectious agents influences behavior

Immune–neural connections: how the immune system’s response to infectious agents influences behavior

Temporal Analysis of Lipopolysaccharide-Induced Sickness Behavior in Virgin and Lactating Female Rats

Oral administration of pentachlorophenol induces interferon signaling mRNAs in C57BL/6 male mouse liver

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