The spleen modulates the febrile response of guinea pigs to LPS

Feleder, Carlos; Li, Zhonghua; Perlik, Vit; Evans, A. W.; Blatteis, Clark M.

doi:10.1152/ajpregu.00378.2002

Cited by 21 publications

(29 citation statements)

References 31 publications

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“…(3) We have shown recently that the onset of LPSinduced fever in guinea pigs is temporally related, irrespective of its routes of administration (intravenous or intraperitoneal), to the appearance of LPS in the liver and its uptake by Kc [72,73], suggesting that the complement system may be activated by contact with LPS in the liver rather than in the bloodstream. This, in turn, suggests that C5 may be generated independently of a plasma-derived complement system, i.e.…”

Section: Discussionmentioning

confidence: 99%

Complement Component C5a Is Integral to the Febrile Response of Mice to Lipopolysaccharide

Boackle²,

Holers³

et al. 2005

Neuroimmunomodulation

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Objectives: The complement system is critical to the febrile response of mice to intraperitoneally administered lipopolysaccharide (LPS). We previously identified C3 and C5 as two components potentially involved in this response. This study was designed to examine whether the complement system is also pivotal in the response of mice to intravenously or intracerebroventricularly injected LPS, to distinguish between C3 and C5 and their cognate derivatives as the essential mediator(s), and to determine whether the failure of complement-deficient mice to develop a fever could be due to their possible inability to secrete pyrogenic cytokines. Methods: Wild-type (WT; C57BL/6J) mice, hypocomplemented or not by intravenously injected cobra venom factor (10 U/mouse), and C3-, CR3- and C5-sufficient and -deficient mice were intravenously challenged with LPS (0.25 µg/mouse); WT and C3–/– mice pretreated with a C5a receptor antagonist (C5aRa) were similarly challenged. In addition, the serum levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 were compared in LPS-treated C5+/+ and C5–/– mice. Results: LPS induced a 1°C rise in core temperature in all the mice, except C5–/– mice and those pretreated with C5aRa. C5+/+ and C5–/– mice challenged intracerebroventricularly with LPS exhibited identical febrile responses. LPS induced similar increases in the serum levels of IL-1β, TNFα and IL-6 in C5+/+ and C5–/– mice. Conclusions: C5a is crucial for the development of febrile responses to LPS in mice; its site of action is peripheral, not central. The possibility that an inability to produce cytokines could account for the failure of C5–/– mice to develop a fever is not supported.

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Section: Discussionmentioning

confidence: 99%

Complement Component C5a Is Integral to the Febrile Response of Mice to Lipopolysaccharide

Boackle²,

Holers³

et al. 2005

Neuroimmunomodulation

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“…In a previous study, we (9) found that removal of the spleen of guinea pigs results in significantly enhanced febrile responses to both iv and ip LPS, and that these hyperpyrexias are associated with an increased uptake of LPS by KC. These effects, moreover, are persistent because their robustness is undiminished 30 days after splenectomy.…”

mentioning

confidence: 83%

“…Unlabeled LPS was Salmonella enteritidis LPS B (batch no. 651628; Difco Laboratories, Detroit, MI), the same LPS batch we used in our previous studies (9,15). The vehicle for all solutions was pyrogenfree saline (PFS, 0.9% NaCl, USP; Abbott Laboratories, Chicago, IL).…”

Section: Drugsmentioning

confidence: 99%

Putative antihyperpyretic factor induced by LPS in spleen of guinea pigs

Feleder¹,

Perlik²,

Ying³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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We reported previously that the onset of LPS-induced fever, irrespective of its route of administration, is temporally correlated with the appearance of LPS in the liver and that splenectomy significantly increases both the febrile response to LPS and the uptake of LPS by Kupffer cells (KC). To further evaluate the role of the spleen in LPS fever production, we ligated the splenic vein and, 7 and 30 days later, monitored the core temperature changes over 6 h after intraperitoneal (ip) injection of LPS (2 microg/kg). Both the febrile response and the uptake of LPS by KC were significantly augmented. Like splenectomy, splenic vein ligation (SVL) increased the febrile response and LPS uptake by KC until the collateral circulation developed, suggesting that the spleen may normally contribute an inhibitory factor that limits KC uptake of LPS and thus affects the febrile response. Subsequently, to verify the presence of this factor, we prepared splenic extracts from guinea pigs pretreated with LPS (8 microg/kg ip) or pyrogen-free saline, homogenized and ultrafiltered them, and injected them intravenously into splenectomized (Splex) guinea pigs pretreated with LPS (8 microg/kg ip). The results confirmed our presumption that the splenic extract from LPS-treated guinea pigs inhibits the exaggerated febrile response and the LPS uptake by the liver of Splex guinea pigs, indicating the presence of a putative splenic inhibitory factor, confirming the participation of the spleen in LPS-induced fever, and suggesting the existence of a novel antihyperpyretic mechanism. Preliminary data indicate that this factor is a lipid.

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“…Moreover, since the liver contains the body's largest population of mononuclear phagocytes (Kupffer cells, Kc), it is the primary clearinghouse of circulating LPS and therefore also the principal source of LPS-induced cytokines; the pyrogenic signal should therefore originate there. Indeed, the essential role of Kc in fever production was recently verified (Feleder et al, 2003;. Furthermore, a number of studies have now established that the subdiaphragmatic section of both vagal trunks, and its hepatic branches in particular, significantly attenuates the febrile response to LPS Sehic and Blatteis, 1996;Romanovsky et al, 1997a, b;Fleshner et al, 1998;Gaykema et al, 1998;Simons et al, 1998;Wieczorek et al, 2005), albeit that it is still controversial whether this effect is conditional on the route and dose of LPS administered (Goldbach et al, 1997;Hansen et al, 2001).…”

Section: Pyrogen Activation Of the Brain: The Role Of The Vagusmentioning

confidence: 99%

The onset of fever: new insights into its mechanism

Blatteis

2007

Progress in Brain Research

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145

103

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Abstract:The classical view of fever production is that it is modulated in the ventromedial preoptic area (VMPO) in response to signaling by pyrogenic cytokines elaborated in the periphery by mononuclear phagocytes and the consequent induction of cyclooxygenase (COX)-2-dependent prostaglandin (PG)E 2 in the VMPO. This mechanism has, however, been questioned, in particular because the appearance of circulating cytokines lags the onset of the febrile response to intravenously (iv) injected bacterial endotoxic lipopolysaccharide (LPS), an exogenous pyrogen. Moreover, COX-2, in this case, is itself an inducible enzyme, the de novo synthesis of which similarly lags significantly the onset of fever. Issues also exist regarding the accessibility of the POA to blood-borne cytokines. New data adduced over the past 10 years indicate that the peripheral febrigenic message is conveyed to the VMPO via a neural rather than a humoral route, specifically by the vagus to the nucleus tractus solitarius (NST), and that the peripheral trigger is PGE 2 , not cytokines; vagal afferents express PGE 2 receptors (EP 3 ). Thus, the initiation of the febrile responses to both iv and intraperitoneal (ip) LPS is temporally correlated with the appearance of LPS in the liver's Kupffer cells (Kc), its arrival immediately activating the complement (C) cascade and the consequent production of the anaphylatoxin C5a; the latter is the direct stimulus for PGE 2 production, catalyzed nondifferentially by constitutive COX-1 and -2. From the NST, the signal proceeds to the VMPO via the ventral noradrenergic bundle, causing the intrapreoptic release of norepinephrine (NE) which then evokes two distinct core temperature (T c ) rises, viz., one a 1 -adrenoceptor (AR)-mediated, rapid in onset, and PGE 2 -independent, and the other a 2 -AR-mediated, delayed, and COX-2/PGE 2 -dependent, i.e., the prototypic febrile pattern induced by iv LPS. The release of NE is itself modulated by nitric oxide contemporaneously released in the VMPO.

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The spleen modulates the febrile response of guinea pigs to LPS

Cited by 21 publications

References 31 publications

Complement Component C5a Is Integral to the Febrile Response of Mice to Lipopolysaccharide

Complement Component C5a Is Integral to the Febrile Response of Mice to Lipopolysaccharide

Putative antihyperpyretic factor induced by LPS in spleen of guinea pigs

The onset of fever: new insights into its mechanism

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