Fever induction by localized subcutaneous inflammation  in guinea pigs: the role of cytokines and prostaglandins

Ross, Günter; Hübschle, Thomas; Pehl, Ulrich; H, Braun; Voigt, Karlheinz; Gerstberger, Rüdiger; Roth, Joachim

doi:10.1152/japplphysiol.00485.2002

Cited by 37 publications

(37 citation statements)

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“…Among the pyrogenic cytokines (TNF, IL-1, or IL-6) that are produced within the site of localized subcutaneous inflammation, IL-6 is the only putative endogenous pyrogen that enters the circulation in significant quantities. It has therefore been proposed that the increase of IL-6 in the bloodstream, albeit moderate, is involved in the manifestation of fever and other brain-controlled signs of illness that occur during localized inflammation (9,34,38).However, the following observations from our previous studies (29,30,34) suggested that, in addition to a humoral signal provided by circulating IL-6, local mechanisms generated directly at the site of subcutaneous inflammation may participate in the transmission of febrile signals to parts of the brain that are involved in fever generation. 1) We tested the effects of two doses of LPS (100 or 10 g/kg) injected into the subcutaneous chamber on body temperature.…”

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confidence: 78%

“…However, the following observations from our previous studies (29,30,34) suggested that, in addition to a humoral signal provided by circulating IL-6, local mechanisms generated directly at the site of subcutaneous inflammation may participate in the transmission of febrile signals to parts of the brain that are involved in fever generation. 1) We tested the effects of two doses of LPS (100 or 10 g/kg) injected into the subcutaneous chamber on body temperature.…”

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confidence: 98%

“…These treatments result in a generalized systemic inflammatory response, which is accompanied by increased measurable amounts of proinflammatory cytokines and LPS in the circulation (10,14,17,28,32). To study a cytokine release within a local area of inflammation, experimental models have been introduced in which LPS is administered locally, rather than systemically, into a subcutaneous air pouch in rats (8,22,23) or a subcutaneously implanted artificial Teflon chamber in guinea pigs (29,30,34). LPS that is injected into the air pouch (8) or the subcutaneous chamber (29) is not measurable in the systemic circulation 1 h after its injection.…”

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confidence: 99%

“…To study a cytokine release within a local area of inflammation, experimental models have been introduced in which LPS is administered locally, rather than systemically, into a subcutaneous air pouch in rats (8,22,23) or a subcutaneously implanted artificial Teflon chamber in guinea pigs (29,30,34). LPS that is injected into the air pouch (8) or the subcutaneous chamber (29) is not measurable in the systemic circulation 1 h after its injection. This observation does, however, not exclude the possibility that a small fraction of the injected LPS might have leaked from the air pouch or the chamber immediately after the injection procedure.…”

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confidence: 99%

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Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

Rummel¹,

Barth²,

Voss³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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In guinea pigs, dose-dependent febrile responses were induced by injection of a high (100 g/kg) or a low (10 g/kg) dose of bacterial lipopolysaccharide (LPS) into artificial subcutaneously implanted Teflon chambers. Both LPS doses further induced a pronounced formation of prostaglandin E 2 (PGE2) at the site of localized subcutaneous inflammation. Administration of diclofenac, a nonselective cyclooxygenase (COX) inhibitor, at different doses (5, 50, 500, or 5,000 g/kg) attenuated or abrogated LPS-induced fever and inhibited LPS-induced local PGE2 formation (5 or 500 g/kg diclofenac). Even the lowest dose of diclofenac (5 g/kg) attenuated fever in response to 10 g/kg LPS, but only when administered directly into the subcutaneous chamber, and not into the site contralateral to the chamber. This observation indicated that a localized formation of PGE 2 at the site of inflammation mediated a portion of the febrile response, which was induced by injection of 10 g/kg LPS into the subcutaneous chamber. Further support for this hypothesis derived from the observation that we failed to detect elevated amounts of COX-2 mRNA in the brain of guinea pigs injected subcutaneously with 10 g/kg LPS, whereas subcutaneous injections of 100 g/kg LPS, as well as systemic injections of LPS (intra-arterial or intraperitoneal routes), readily caused expression of the COX-2 gene in the guinea pig brain, as demonstrated by in situ hybridization. Therefore, fever in response to subcutaneous injection of 10 g/kg LPS may, in part, have been evoked by a neural, rather than a humoral, pathway from the local site of inflammation to the brain. lipopolysaccharide; febrile response; prostaglandin E 2; cyclooxygenase-2; immune system-to-brain communication MOST EXPERIMENTAL STUDIES employing bacterial lipopolysaccharide (LPS) to induce fever use a systemic route of administration, such as intraperitoneal, intravenous, or intra-arterial injections of the pyrogen. These treatments result in a generalized systemic inflammatory response, which is accompanied by increased measurable amounts of proinflammatory cytokines and LPS in the circulation (10,14,17,28,32). To study a cytokine release within a local area of inflammation, experimental models have been introduced in which LPS is administered locally, rather than systemically, into a subcutaneous air pouch in rats (8,22,23) or a subcutaneously implanted artificial Teflon chamber in guinea pigs (29,30,34). LPS that is injected into the air pouch (8) or the subcutaneous chamber (29) is not measurable in the systemic circulation 1 h after its injection. This observation does, however, not exclude the possibility that a small fraction of the injected LPS might have leaked from the air pouch or the chamber immediately after the injection procedure. Among the pyrogenic cytokines (TNF, IL-1, or IL-6) that are produced within the site of localized subcutaneous inflammation, IL-6 is the only putative endogenous pyrogen that enters the circulation in significant quantities. It has therefore been proposed that...

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confidence: 78%

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confidence: 98%

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confidence: 99%

mentioning

confidence: 99%

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Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

Rummel¹,

Barth²,

Voss³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…We (6,50) and others (12,44) have suggested that, alternatively, PGE 2 could be that mediator. It is synthesized by all macrophages, including Kc, in response to LPS (46), and its levels in plasma are correlated with the febrile course (35).…”

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confidence: 84%

LPS-activated complement, not LPS per se, triggers the early release of PGE₂by Kupffer cells

Perlik¹,

Li²,

Goorha³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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The intravenous injection of LPS rapidly evokes fever. We have hypothesized that its onset is mediated by prostaglandin (PG)E2 quickly released by Kupffer cells (Kc). LPS, however, does not stimulate PGE2 production by Kc as rapidly as it induces fever; but complement (C) activated by LPS could be the exciting agent. To test this hypothesis, we injected LPS (2 or 8 g/kg) or cobra venom factor (CVF, an immediate activator of the C cascade that depletes its substrate, ultimately causing hypocomplementemia; 25 U/animal) into the portal vein of anesthetized guinea pigs and measured the appearance of PGE2, TNF-␣, IL-1␤, and IL-6 in the inferior vena cava (IVC) over the following 60 min. LPS (at both doses) and CVF induced similar rises in PGE2 within the first 5 min after treatment; the rises in PGE2 due to CVF returned to control in 15 min, whereas PGE2 rises due to LPS increased further, then stabilized. LPS given 3 h after CVF to the same animals also elevated PGE2, but after a 30-to 45-min delay. CVF per se did not alter basal PGE2 and cytokine levels and their responses to LPS. These in vivo effects were substantiated by the in vitro responses of primary Kc from guinea pigs to C (0.116 U/ml) and LPS (200 ng/ml). These results indicate that LPS-activated C rather than LPS itself triggers the early release of PGE2 by Kc. liver; fever; portal vein cannulation; cobra venom factor; pyrogenic cytokines FEVER DEVELOPS QUICKLY AFTER the intravenous bolus administration of a pyrogenic dose of LPS to conscious guinea pigs, rats, and other species, but the afferent mechanism that induces this response is controversial. It is generally thought that it is mediated by pyrogenic cytokines produced secondarily in response to the LPS challenge, rather than by its direct action. Tumor necrosis factor-␣ (TNF-␣), IL-1␤, and IL-6 are the major cytokines implicated in this response (9). There is, however, a temporal disconnect between the first appearance of these cytokines and the onset of the febrile response to intravenous LPS; that is, fever appears within 10 -15 min (13, 51) whereas TNF-␣, the first cytokine to appear, is not detectable until 30 min after LPS treatment (18,23,24,39). This temporal discrepancy is less evident after the intraperitoneal administration of low to moderate doses of LPS, when the latency of fever onset is ϳ60 min but becomes evident also when higher doses are administered, when the onset latency approaches that after intravenous LPS (7).We have shown previously that the onsets of the febrile responses to intravenous and intraperitoneal LPS are correlated with the appearance of LPS in the liver's Kupffer cells (Kc) (31), the body's principal clearinghouse of LPS (16,34,45) and source of pyrogenic cytokines (10). As cytokines are not constitutively expressed by Kc and their de novo production occurs after some delay (32), we and others have proposed, to account for the promptness of the febrile response to intravenous LPS, that the peripheral pyrogenic signal could be transmitted to the preoptic-anterior...

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Selective contribution of interleukin‐6 and leptin to brain inflammatory signals induced by systemic LPS injection in mice

Rummel

Inoue

Sachot

et al. 2008

J of Comparative Neurology

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This study aimed to address the relative contributions of the proinflammatory cytokine interleukin-6 (IL-6) and the cytokine-like hormone leptin to the genomic activation of brain cells during lipopolysaccharide (LPS)-induced systemic inflammation. Wildtype and IL-6KO mice were injected with LPS (50 microg/kg, intraperitoneally) and the brains analyzed by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). LPS induced a pronounced nuclear translocation of the signal transducer and activator of transcription (STAT3) throughout the brains of wildtype mice, an effect that was significantly diminished, but not abolished, in the IL-6KOs. The remnant STAT3-activation, although still observed within some of the same areas activated by IL-6, was most intense in ependymal and meningial cells and along distinct blood vessels throughout the brain. This expression was almost totally abolished in the presence of an anti-leptin antiserum. Interestingly, the induction of cyclooxygenase 2 and microsomal prostaglandin E synthase (mPGES), the rate-limiting enzymes for synthesis of PGE2 by LPS, was diminished to a degree that correlated with the absence of IL-6 but not entirely with leptin. These results demonstrate that the induction of the inflammatory pathway in the brain is mediated by both IL-6 and leptin, which appear to work in tandem. Unlike IL-6, however, the contribution of leptin to this response was limited to distinct cell types/brain areas and STAT3-responsive target genes implicated in the brain-controlled sickness-type response. The physiological significance of leptin's action on meningeal and endothelial cells remains to be clarified but might reflect a role in LPS-induced immune cell infiltration into the brain.

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Fever induction by localized subcutaneous inflammation in guinea pigs: the role of cytokines and prostaglandins

Cited by 37 publications

References 37 publications

Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

LPS-activated complement, not LPS per se, triggers the early release of PGE₂by Kupffer cells

Selective contribution of interleukin‐6 and leptin to brain inflammatory signals induced by systemic LPS injection in mice

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Fever induction by localized subcutaneous inflammation in guinea pigs: the role of cytokines and prostaglandins

Cited by 37 publications

References 37 publications

Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

LPS-activated complement, not LPS per se, triggers the early release of PGE2by Kupffer cells

Selective contribution of interleukin‐6 and leptin to brain inflammatory signals induced by systemic LPS injection in mice

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LPS-activated complement, not LPS per se, triggers the early release of PGE₂by Kupffer cells