Kupffer cell-generated PGE₂triggers the febrile response of guinea pigs to intravenously injected LPS

Abstract

Because the onset of fever induced by intravenously (i.v.) injected bacterial endotoxic lipopolysaccharides (LPS) precedes the appearance in the bloodstream of pyrogenic cytokines, the presumptive peripheral triggers of the febrile response, we have postulated previously that, in their stead, PGE2 could be the peripheral fever trigger because it appears in blood coincidentally with the initial body core temperature (Tc) rise. To test this hypothesis, we injected Salmonella enteritidis LPS (2 microg/kg body wt i.v.) into conscious guinea pigs and measured their plasma levels of LPS, PGE2, TNF-alpha, IL-1beta, and IL-6 before and 15, 30, 60, 90, and 120 min after LPS administration; Tc was monitored continuously. The animals were untreated or Kupffer cell (KC) depleted; the essential involvement of KCs in LPS fever was shown previously. LPS very promptly (<10 min) induced a rise of Tc that was temporally correlated with the elevation of plasma PGE2. KC depletion prevented the Tc and plasma PGE2 rises and slowed the clearance of LPS from the blood. TNF-alpha was not detectable in plasma until 30 min and in IL-1beta and IL-6 until 60 min after LPS injection. KC depletion did not alter the times of appearance or magnitudes of rises of these cytokines, except TNF-alpha, the maximal level of which was increased approximately twofold in the KC-depleted animals. In a follow-up experiment, PGE2 antiserum administered i.v. 10 min before LPS significantly attenuated the febrile response to LPS. Together, these results support the view that, in guinea pigs, PGE2 rather than pyrogenic cytokines is generated by KCs in immediate response to i.v. LPS and triggers the febrile response.

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

“…It has also been established that hepatic vagal afferents are necessary to promptly convey information from the immune system to the hypothalamus and initiate a fever in response to peripheral LPS exposure (Simons et al, 1998;MohanKumar et al, 2000). In this regard it appears that interleukin-1beta or PGE 2 stimulates the vagus (Li et al, 2006;Wieczorek and Dunn, 2006), and these noradrenergic pathways project from the brainstem through the ventral noradrenergic bundle and synapse in the POAH, where there are numerous noradrenergic terminals (Kumar et al, 2007). Our work suggests that norepinephrine released from these projections may act quickly and directly at alpha-1 ARs to modulate the activity of thermosensitive and insensitive neurons to shift the set-point into a hyperthermic range.…”

“…New evidence suggests this peripheral febrile message is relayed to the hypothalamus via a much faster neural route, through the hepatic vagus to the nucleus tractus solitarius (NST; Blatteis, 2007). Upon arrival in the liver, LPS is taken up by Kupffer cells (Kc) and a complement cascade is activated, promoting Kc to release PGE 2 and stimulate hepatic vagal afferents that project to the POAH (Li et al, 2006). It is then the release of norepinephrine via the hepatic vagus which mediates this response to peripheral LPS (Feleder et al, 2007).…”

Behavioral fever in ectothermic vertebrates

“…Its signaling starts with the recognition of pathogen-associated molecular patterns (PAMPs) and/or damageassociated molecular patterns (DAMPs) by immune cells (Atkins and Bodel, 1979;Blatteis, 2006). These stimuli, named exogenous pyrogens, are detected through germline-encoded pattern recognition receptors (PRR), a.e.…”

“…Both COX2 (Steiner et al, 2005) and mPGES1 (Engblom et al, 2003) were shown to be indispensable for LPS-induced fever. In addition to the PGE 2 locally produced in the brain, PGE 2 can also be secreted at the periphery predominantly by hepatic and pulmonary macrophages (Li et al, 2006;Simm et al, 2016;Steiner et al, 2006). This peripheral PGE 2 binds to albumin which protects it from enzymatic degradation during its journey to the brain via the bloodstream (Ivanov and Romanovsky, 2004).…”

Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways

“…This recognition mobilizes a cascade of events beginning with generation of complement (Blatteis et al, 2004), prostaglandin E 2 (PGE 2 ) (Li et al, 2006;Steiner et al, 2006), and the proinflammatory cytokines, tumor necrosis factor ␣, interleukin (IL)-1␤, and IL-6 (Luheshi, 1998;Dinarello, 1999). These downstream products of TLR4 activation activate the brain and vagal afferents (for review, see Maier et al, 1998) to induce further synthesis of prostaglandins (Cao et al, 1997;Matsumura et al, 2000;Yamagata et al, 2001) and cytokines within the brain that cause fever and sickness behavior (Dantzer et al, 2008).…”