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Mechanisms of Fever Production and Lysis: Lessons from Experimental LPS Fever

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Abstract

Fever is a cardinal symptom of infectious or inflammatory insults, but it can also arise from noninfectious causes. The fever‐inducing agent that has been used most frequently in experimental studies designed to characterize the physiological, immunological and neuroendocrine processes and to identify the neuronal circuits that underlie the manifestation of the febrile response is lipopolysaccharide (LPS). Our knowledge of the mechanisms of fever production and lysis is largely based on this model. Fever is usually initiated in the periphery of the challenged host by the immediate activation of the innate immune system by LPS, specifically of the complement (C) cascade and Toll‐like receptors. The first results in the immediate generation of the C component C5a and the subsequent rapid production of prostaglandin E2 (PGE2). The second, occurring after some delay, induces the further production of PGE2 by induction of its synthesizing enzymes and transcription and translation of proinflammatory cytokines. The Kupffer cells (Kc) of the liver seem to be essential for these initial processes. The subsequent transfer of the pyrogenic message from the periphery to the brain is achieved by neuronal and humoral mechanisms. These pathways subserve the genesis of early (neuronal signals) and late (humoral signals) phases of the characteristically biphasic febrile response to LPS. During the course of fever, counterinflammatory factors, “endogenous antipyretics,” are elaborated peripherally and centrally to limit fever in strength and duration. The multiple interacting pro‐ and antipyretic signals and their mechanistic effects that underlie endotoxic fever are the subjects of this review. © 2014 American Physiological Society. Compr Physiol 4:1563‐1604, 2014.

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Figure 1. Figure 1. Classical concept of fever induction. According to the classical concept, fever develops in sequential steps, starting with the entry of an exogenous pyrogen, for example, LPS, into the host through a break in one of its natural barriers (1). This exogenous agent is transported to the liver and there activates Kupffer cells (Kc) and, on the way, other mononuclear phagocytic cells to produce endogenous pyrogens (IL‐1, IL‐6, and TNF). These then are released into the bloodstream (2) and transported to the POA (3), where they induce the expression of COX‐2 and, hence, PGE2. PGE2, in turn, inhibits the activity of warm‐sensitive neurons (W), causing heat conservation (and reflexly heat production [not shown]) and thereby acting as the proximal mediator of fever (4). (Adapted from Ref. with permission.)
Figure 2. Figure 2. Thermoeffector responses during the course of LPS‐induced fever in a rabbit. The febrile response to the intravenous injection of 1 μg/kg of LPS into a rabbit sitting unrestrained in a rabbit box kept at 28°C and with back skin and ears exposed to a room temperature of 25°C. The development and maintenance of fever (from 10 to 120 min after injection) are achieved by the activation of thermoeffector responses that (a) increase heat‐production (increased oxygen consumption and shivering [increased electromyographical muscle activity, EMA]) and (b) decrease heat dissipation (reduction of ear skin blood flow and decrease of respiratory rate). Dotted line: response of a sympathectomized ear, indicating the role of sympathetic tone in the control of the thermoregulatory reduction of ear skin blood flow. (Reproduced from Ref. , with permission from De Gruyter).
Figure 3. Figure 3. Thermoregulatory thresholds in normothermy and fever. Upper panel: Thermoregulatory thresholds, that is, Tcs at which heat production and heat dissipation mechanisms are activated in normothermic subjects when exposed to cold and heat, respectively. The interthreshold zone is narrow under these conditions. Lower panel: During the early phase of fever, there occurs a symmetric shift of thermoregulatory thresholds for heat production and heat dissipation to higher Tc values. During the late phase of fever, the interthreshold zone widens, the threshold for thermolytic responses remaining elevated, but that for the activation of thermogenic responses decreasing (for details see: Ref. ).
Figure 4. Figure 4. Clinical fever patterns. Clinical fever patterns and examples of diseases that are accompanied by a given pattern (for details see: Ref. ).
Figure 5. Figure 5. Experimentally induced fever by injections of LPS via different routes. LPS (L) was injected intra‐arterially (ia), intraperitoneally (i.p.), or subcutaneously (s.c.) into several groups of guinea pigs. The numbers (L10, L30, and L100) refer to the injected dose of LPS in μg/kg. Note the biphasic shapes and the rapid onsets of the LPS‐induced febrile responses; fever durations and heights, however, are little affected in these instances (reproduced from Ref. , with permission from Wiley).
Figure 6. Figure 6. Schematic illustration of the structure of a Toll‐like receptor. The extracellular domains of all TLRs comprise leucine‐rich repeats (LRR) and one or two cysteine‐rich regions (CRR). The intracellular domain of a TLR is highly similar to the cytoplasmatic region of the IL‐1‐receptor (“Toll/IL‐1 receptor” domain, TIR).
Figure 7. Figure 7. Stimulation of Kc by LPS via TLR4 (left) and via complement activation (right). The complement‐mediated pathway results in formation of PGE2 within minutes. This occurs via the hydrolysis by membrane‐associated phospholipase C (PLC), which is activated by C5a (complement factor 5a), but not LPS or cytokines. Arachidonic acid (AA) liberation by PLC is 10 times more rapid than that mediated by phospholipase A2, the enzyme that is activated by LPS via TLR4. The subsequent conversion of AA to PGE2 is catalyzed by COX‐1 and COX‐2, both expressed constitutively in Kc. The TLR4‐mediated pathway induces de novo synthesis of pyrogenic cytokines, COX‐2, iNOS, and other molecules; the latter process of formation of PGE2 requires at least 30 min. (From Ref. with permission from Elsevier.)
Figure 8. Figure 8. Production of PGE2 by murine Kupffer cells under in vitro conditions induced by stimulation with C alone, or with C + LPS or cytokines (IL‐1β or IL‐18), the latter in the absence or presence of C. Note that PGE2 was detectable within 2 min after the addition of C alone or of C + LPS or cytokines. LPS or cytokines alone caused only minor elevations of PGE2 after 1 h. Since COX‐1 and ‐2 gene deletions did not prevent these responses (see: Blatteis 2006), both constitutive COX‐1 and ‐2 can very rapidly catalyze the production of PGE2 by C‐activated Kc. (Reproduced from Ref. , with permission from Elsevier.)
Figure 9. Figure 9. Schematic illustration of a proposed fever‐inducing pathway as a critical component of the thermoregulatory system. According to Ref. , the thermoregulatory system consist of three components, that is, the afferent sensory part starting in the skin, the central integrative part, and the efferent part responsible to control thermoeffector organs. Under the influence of peripheral cooling or of the appearance of PGE2 within the MnPO, efferent pathways are activated which promote heat production via shivering and/or nonshivering thermogenesis and skin vasoconstriction (for details see: text and Table ; from Ref. , with permission of the American Physiological Society).
Figure 10. Figure 10. Location of sensory CVOs in the brain. Schematic illustration of the location of brain regions that lack a tight blood‐brain barrier in a midsaggital section through the rat brain. These structures are highlighted by red color (AP = area postrema; ME = median eminence; NL = neural lobe of the pituitary; OVLT = organum vasculosum laminae terminalis; PIN = pineal organ; SFO = subfornical organ; SCO = subcommissural organ). OVLT and AP are highlighted by blue circles, the OVLT because of its close vicinity to the POA (humoral hypothesis of fever generation), the AP because of its functional connectivity with the nucleus of the solitary tract, NTS (afferent neuronal hypothesis of fever generation).
Figure 11. Figure 11. Content of norepinephrine (NE) in microdialysate effluents collected over 6 h at 30‐min intervals from the POA of conscious guinea pigs treated with pyrogen‐free saline (PFS) or LPS (2 μg/kg, iv) at time 0 min. Note that the NE‐peak seen in LPS‐treated guinea pigs mirrors the first phase of LPS‐fever (aCSF = artificial cerebrospinal fluid). (Reproduced from Ref. , with permission of the American Physiological Society.)
Figure 12. Figure 12. Schematic illustration of the cellular and molecular events involved in the central processing of the pyrogenic message conveyed to the brain via the vagus. According to this hypothesis, fever is initiated (“fast,” first phase) via the inhibitory effect of NE on warm‐sensitive (WS) neurons. Fever is maintained via induced formation of PGE2 (“slow,” second phase), again by an inhibitory effect on WS (FR, firing rate, FR). NO, on the other hand, inhibits the release of NE and formation of PGE2, thus exerting antipyretic effects. Reactive oxygen species (ROS) may cause an early increase of PGE2 during the first fever phase, which is, however, not relevant for the initiation of fever (see text for further details, from Ref. , with permission).


Figure 1. Classical concept of fever induction. According to the classical concept, fever develops in sequential steps, starting with the entry of an exogenous pyrogen, for example, LPS, into the host through a break in one of its natural barriers (1). This exogenous agent is transported to the liver and there activates Kupffer cells (Kc) and, on the way, other mononuclear phagocytic cells to produce endogenous pyrogens (IL‐1, IL‐6, and TNF). These then are released into the bloodstream (2) and transported to the POA (3), where they induce the expression of COX‐2 and, hence, PGE2. PGE2, in turn, inhibits the activity of warm‐sensitive neurons (W), causing heat conservation (and reflexly heat production [not shown]) and thereby acting as the proximal mediator of fever (4). (Adapted from Ref. with permission.)


Figure 2. Thermoeffector responses during the course of LPS‐induced fever in a rabbit. The febrile response to the intravenous injection of 1 μg/kg of LPS into a rabbit sitting unrestrained in a rabbit box kept at 28°C and with back skin and ears exposed to a room temperature of 25°C. The development and maintenance of fever (from 10 to 120 min after injection) are achieved by the activation of thermoeffector responses that (a) increase heat‐production (increased oxygen consumption and shivering [increased electromyographical muscle activity, EMA]) and (b) decrease heat dissipation (reduction of ear skin blood flow and decrease of respiratory rate). Dotted line: response of a sympathectomized ear, indicating the role of sympathetic tone in the control of the thermoregulatory reduction of ear skin blood flow. (Reproduced from Ref. , with permission from De Gruyter).


Figure 3. Thermoregulatory thresholds in normothermy and fever. Upper panel: Thermoregulatory thresholds, that is, Tcs at which heat production and heat dissipation mechanisms are activated in normothermic subjects when exposed to cold and heat, respectively. The interthreshold zone is narrow under these conditions. Lower panel: During the early phase of fever, there occurs a symmetric shift of thermoregulatory thresholds for heat production and heat dissipation to higher Tc values. During the late phase of fever, the interthreshold zone widens, the threshold for thermolytic responses remaining elevated, but that for the activation of thermogenic responses decreasing (for details see: Ref. ).


Figure 4. Clinical fever patterns. Clinical fever patterns and examples of diseases that are accompanied by a given pattern (for details see: Ref. ).


Figure 5. Experimentally induced fever by injections of LPS via different routes. LPS (L) was injected intra‐arterially (ia), intraperitoneally (i.p.), or subcutaneously (s.c.) into several groups of guinea pigs. The numbers (L10, L30, and L100) refer to the injected dose of LPS in μg/kg. Note the biphasic shapes and the rapid onsets of the LPS‐induced febrile responses; fever durations and heights, however, are little affected in these instances (reproduced from Ref. , with permission from Wiley).


Figure 6. Schematic illustration of the structure of a Toll‐like receptor. The extracellular domains of all TLRs comprise leucine‐rich repeats (LRR) and one or two cysteine‐rich regions (CRR). The intracellular domain of a TLR is highly similar to the cytoplasmatic region of the IL‐1‐receptor (“Toll/IL‐1 receptor” domain, TIR).


Figure 7. Stimulation of Kc by LPS via TLR4 (left) and via complement activation (right). The complement‐mediated pathway results in formation of PGE2 within minutes. This occurs via the hydrolysis by membrane‐associated phospholipase C (PLC), which is activated by C5a (complement factor 5a), but not LPS or cytokines. Arachidonic acid (AA) liberation by PLC is 10 times more rapid than that mediated by phospholipase A2, the enzyme that is activated by LPS via TLR4. The subsequent conversion of AA to PGE2 is catalyzed by COX‐1 and COX‐2, both expressed constitutively in Kc. The TLR4‐mediated pathway induces de novo synthesis of pyrogenic cytokines, COX‐2, iNOS, and other molecules; the latter process of formation of PGE2 requires at least 30 min. (From Ref. with permission from Elsevier.)


Figure 8. Production of PGE2 by murine Kupffer cells under in vitro conditions induced by stimulation with C alone, or with C + LPS or cytokines (IL‐1β or IL‐18), the latter in the absence or presence of C. Note that PGE2 was detectable within 2 min after the addition of C alone or of C + LPS or cytokines. LPS or cytokines alone caused only minor elevations of PGE2 after 1 h. Since COX‐1 and ‐2 gene deletions did not prevent these responses (see: Blatteis 2006), both constitutive COX‐1 and ‐2 can very rapidly catalyze the production of PGE2 by C‐activated Kc. (Reproduced from Ref. , with permission from Elsevier.)


Figure 9. Schematic illustration of a proposed fever‐inducing pathway as a critical component of the thermoregulatory system. According to Ref. , the thermoregulatory system consist of three components, that is, the afferent sensory part starting in the skin, the central integrative part, and the efferent part responsible to control thermoeffector organs. Under the influence of peripheral cooling or of the appearance of PGE2 within the MnPO, efferent pathways are activated which promote heat production via shivering and/or nonshivering thermogenesis and skin vasoconstriction (for details see: text and Table ; from Ref. , with permission of the American Physiological Society).


Figure 10. Location of sensory CVOs in the brain. Schematic illustration of the location of brain regions that lack a tight blood‐brain barrier in a midsaggital section through the rat brain. These structures are highlighted by red color (AP = area postrema; ME = median eminence; NL = neural lobe of the pituitary; OVLT = organum vasculosum laminae terminalis; PIN = pineal organ; SFO = subfornical organ; SCO = subcommissural organ). OVLT and AP are highlighted by blue circles, the OVLT because of its close vicinity to the POA (humoral hypothesis of fever generation), the AP because of its functional connectivity with the nucleus of the solitary tract, NTS (afferent neuronal hypothesis of fever generation).


Figure 11. Content of norepinephrine (NE) in microdialysate effluents collected over 6 h at 30‐min intervals from the POA of conscious guinea pigs treated with pyrogen‐free saline (PFS) or LPS (2 μg/kg, iv) at time 0 min. Note that the NE‐peak seen in LPS‐treated guinea pigs mirrors the first phase of LPS‐fever (aCSF = artificial cerebrospinal fluid). (Reproduced from Ref. , with permission of the American Physiological Society.)


Figure 12. Schematic illustration of the cellular and molecular events involved in the central processing of the pyrogenic message conveyed to the brain via the vagus. According to this hypothesis, fever is initiated (“fast,” first phase) via the inhibitory effect of NE on warm‐sensitive (WS) neurons. Fever is maintained via induced formation of PGE2 (“slow,” second phase), again by an inhibitory effect on WS (FR, firing rate, FR). NO, on the other hand, inhibits the release of NE and formation of PGE2, thus exerting antipyretic effects. Reactive oxygen species (ROS) may cause an early increase of PGE2 during the first fever phase, which is, however, not relevant for the initiation of fever (see text for further details, from Ref. , with permission).
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Joachim Roth, Clark M. Blatteis. Mechanisms of Fever Production and Lysis: Lessons from Experimental LPS Fever. Compr Physiol 2014, 4: 1563-1604. doi: 10.1002/cphy.c130033