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Fever, Immunity, and Molecular Adaptations

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Abstract

The heat shock response (HSR) is an ancient and highly conserved process that is essential for coping with environmental stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms temporarily subject themselves to thermal stress in the face of infections. We review the phylogenetically conserved mechanisms that regulate fever and discuss the effects that febrile‐range temperatures have on multiple biological processes involved in host defense and cell death and survival, including the HSR and its implications for patients with severe sepsis, trauma, and other acute systemic inflammatory states. Heat shock factor‐1, a heat‐induced transcriptional enhancer is not only the central regulator of the HSR but also regulates expression of pivotal cytokines and early response genes. Febrile‐range temperatures exert additional immunomodulatory effects by activating mitogen‐activated protein kinase cascades and accelerating apoptosis in some cell types. This results in accelerated pathogen clearance, but increased collateral tissue injury, thus the net effect of exposure to febrile range temperature depends in part on the site and nature of the pathologic process and the specific treatment provided. © 2014 American Physiological Society. Compr Physiol 4:109‐148, 2014.

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Figure 1. Figure 1. Phylogenetic relationship of fever, heat shock, and innate and adaptive immunity. The modern day animals that utilize fever as a strategy for coping with infection are pictorially displayed with supporting references. The approximate phylogenetic ages of fever (600 million years) and related biological processes are shown.
Figure 2. Figure 2. Schematic diagram of thermoregulatory pathway including mechanism of fever regulation. See text for full discussion. To simplify, we have excluded the spinothalamocortical pathway. Abbreviations: Ach, acetycholine; BAT, brown adipose tissue thermogenesis; BBB, blood:brain barrier; DG, dorsal ganglion; DMH, dorsomedial hypothalamus; GABA, gamma‐amino butyric acid inhibitory synapse; glu, glutatergic excitatory synapse; IS, temperature‐insensitive pacemaker neuron; LPBd, dorsal subnucleus of the lateral parabrachial nucleus; LBPel, lateral external subnucleus of the LBP; MnPO, median preoptic nucleus of the hypothalamus; NA, noradrenaline; POA, preoptic area of the hypothalamus; rMR, rostral medullary raphe region; TRP, transient receptor potential channel; WS, warm‐sensing pacemaker neuron.
Figure 3. Figure 3. Effect of Febrile‐range hyperthermia (FRH) on pathogen clearance and host survival in mouse models of bacterial peritonitis and pneumonia. (A) The mouse FRH model in which mice in standard cages are transferred to infant incubators set at 37°C and mice then are inoculated with Klebsiella pneumoniae Caroli strain. Mice were inoculated with 100 cfu via i.p injection (B and C) or 250 cfu via i.t. instillation (D and E) and mice were housed at 23 or 37°C ambient temperature. Survival (C and E) was determined and bacterial colony counts were determined in peritoneal fluid (B) and lung homogenates (D). The p value for the survival studies is shown. The bacterial colony counts are mean ± SE of six experiments. * denotes p < 0.05 versus FRH. (F) To analyze direct effect of temperature on bacterial growth rate, 100 mL aliquots of LB medium were inoculated with 10 cfu K. pneumoniae, incubated at 37 or 39.5°C, and OD650 sequentially measured. (G) Core temperature in four mice per group housed at 23°C (NT) or 37°C (FRH). Coexposure to FRH accelerated pathogen clearance in both the pneumonia and peritonitis models but only improved survival in the peritonitis model. Reprinted in modified form with permission from references and .
Figure 4. Figure 4. Effect of FRH on neutrophil recruitment. Mice were exposed to >95% oxygen (A) or received 50 μg LPS via i.t. instillation (B) and were housed at 23° (NT) or 37°C (FRH) ambient temperature for the indicated time before euthanasia, lung lavage, and quantitation of lavage neutrophil content. Mean ± SE of eight (hyperoxia) or six mice per time point. * denotes p < 0.05 versus NT. (C) IL‐8‐directed trans‐alveolar migration capacity was measured in NT mice and mice exposed to FRH for the indicated time and returned to NT conditions by instilling 1 μg recombinant human IL‐8 via i.t. instillation and quantifying lung lavage neutrophil content 4 h later. Mean ± SE eight mice per group. * denotes p < 0.05 versus time 0 (prewarming). (D) To determine whether the FRH increased neutrophil migration capacity through effects on neutrophils or endothelium we performed neutrophil transfer experiments between NT and FRH. Recipient or donor mice were exposed to FRH for 24 h, donor PMNs isolated, fluorescently labeled, and injected via tail vein, and IL‐8‐directed donor PMN TAM determined by flow cytometry and manual neutrophil counts. The donor/recipient treatment is indicated on the x‐axis. Mean±SE; six mice per group. * denotes p < 0.05 versus all other groups. (E) To determine the participation of ERK and p38 MAP kinases in FRH‐augmented neutrophil migration, groups of 8 mice were untreated or treated with 2% DMSO (sham), 200 μg U0126 or 1 mg SB203580 (SB) 30 min before 16 h FRH or normothermic exposure and IL‐8‐directed PMN transalveolar migration was measured. Mean±SE. * and † denotes p < 0.05 versus normothermic and untreated mice, respectively. (F) Inflation‐fixed lungs from normothermic (NT) and 24 h‐FRH‐exposed mice 4 h after intratracheal IL‐8 instillation were stained for GR‐1 (PMNs, red) and VE‐cadherin (ECs, green), and analyzed by confocal microscopy. White and yellow arrows denote intravascular and extravasating PMNs, respectively. (G) Human Microvascular Lung Endothelial Cells (HMVEC‐Ls) were incubated at 39.5°C for indicated time or treated with 1 ng/ml TNFα for 6 h at 37°C and IL‐8 directed transendothelial migration of calcein AM‐stained human neutrophils measured over 2 h at 37°C and standardized to untreated HMVEC‐Ls. Mean±SE; four experiments. * and † denote p < 0.05 versus time‐0 and TNFα. (H) HMVEC‐Ls were untreated (Control) or pretreated for 30 min with DMSO, U0126, or SB203580 (SB), incubated for 24 h at 37°C or 39.5°C, and neutrophil transendothelial migration measured. Mean±SE; four experiments. * and † denote p < 0.05 versus 37°C and untreated 39.5°C. Coexposure to FRH increases capacity for chemokine‐directed neutrophil migration through effects on neutrophils and endothelium. Reprinted in modified form with permission from references and .
Figure 5. Figure 5. Effect of FRH on pulmonary vascular endothelial permeability. Mice were exposed to >95% oxygen (A) or received 50 μg LPS via i.t. instillation (B) and were housed at 23° (NT) or 37°C (FRH) ambient temperature for the indicated time before euthanasia, lung lavage, and quantitation of lavage neutrophil content. Mean ± SE of eight (hyperoxia) or six mice per time point. * and † denote p < 0.05 versus NT and time 0, respectively. (C) HMVECLs were incubated with the indicated concentration of TNFα for 6h at 37 or 39.5°C, the TNFα was removed and transendothelial flux of 10 kDa Cascade blue dextran over 30 min at 37°C was measured. (D) HMVEC‐Ls were incubated with 0.25 U/mL TNFα for 6 h at the indicated temperature and 10 kDa Cascade blue flux measured. Mean ± SE, n = 21. * and † denote changes with TNFα‐free controls and 37°C cells, respectively. (E) HMVECLs were incubated for 6 h with either 2.5 U/mL TNFα at 37°C or 0.25 U/mL TNFα at 39.5°C, the TNFα was removed, all monolayers returned to 37°C and 10 kDa Cascade blue dextran flux measured immediately and then sequentially during recovery. Mean ± SE, n = 9. * denotes p < 0.05 versus 39.5°C at time 0. (F) HMVECLs were pretreated with 10 μmol/L UO126 or p38 MAPK SB203580 for 30 min at 37°C, then incubated with 0.25 U/mL TNFα for 6 h at the indicated temperature, the TNFα was removed and 10 kDa Cascade blue dextran flux measured. Mean ± SE, n = 9. * and † denote p < 0.05 versus TNFα‐free controls and 37°C cells, respectively. (G) HMVECLs grown on chamber slides were incubated for 6 h without or with 0.25 U/mL TNFα at 37°C or 39.5°C, fixed and stained with phalloidin coupled with Alexafluor488, counterstained with DAPI, and visualized by fluorescent confocal microscopy. Intercellular gaps are noted by the arrows. (H) F‐actin staining intensity from panel G quantified and expressed relative to 37°C without TNFα. Mean±SE, n = 4. † and ‡ denote p < 0.05 versus 37°C with and without TNFα, respectively. Coexposure to FRH reversibly increases endothelial permeability. Reprinted in modified form with permission from references .
Figure 6. Figure 6. Effect of FRH on epithelial apoptosis. (A‐C) Mice received 50 μg LPS via i.t. instillation and were housed at 23 or 37°C ambient temperature for 48 h, the lungs were then inflation fixed and stained with hematoxalyn and eosin. A is untreated control, B and C are normothermic and FRH‐exposed mice, respectively. Arrows indicate loss of cilia and distinct nuclei. (D) Mouse MLE15 epithelial cells were incubated with indicated concentration of recombinant mouse TNFα for 24 h at 37 or 39.5°C and survival assessed by crystal violet staining and measuring absorbance at 570 nm. Mean ± SE. Survival was different with p < 0.05 by MANOVA. (E and F) MLE15 cells were incubated for indicated time at 37° or 39.5°C with or without 2 ng/mL TNFα, lysed, and immunobloted for active caspase‐3 (C3), PARP, and β‐tubulin (E) or caspase‐8 (F). Thick and thin arrows indicate full‐length and cleaved PARP and caspase‐8. Coexposure to FRH enhances LPS‐induced lung epithelial injury in vivo and accelerates TNFα‐induced apoptosis in lung epithelial cells in vitro. Reprinted in modified form with permission from references .
Figure 7. Figure 7. FRH enhances lymphocyte trafficking to the lymph high endothelial venule (HEV). (A) BALB/c mice were exposed to FRH (whole body hyperthermia, WBH) for 6 h and the total number of lymphocytes in peripheral blood (PB), peripheral lymph node (PLN), and spleen was quantified. Lymphocyte expression of L‐selectin and α4β7 integrin was analyzed by flow cytometry. Mean ±SE of three experiments. * and ** denote p < 0.02 and 0.03 versus control. (B) Intravital microscopy (left) of the interactions of calcein‐labeled splenocytes with the lymph node venular tree of an WBH‐treated mouse, showing the vascular structure, including the superficial epigastric artery (SEA), superficial epigastric vein (SEV) and venular branches (I‐V) in an inguinal lymph node. Right, rolling fractions and sticking fractions in normothermic (NT) and WBH‐treated mice. Mean ±SE, three mice per group. * and ** denote p < 0.0001, and p < 0.01, normothermic versus NT. (C) Expression of trafficking molecules in NT or FRH‐treated mice was analyzed by scanning confocal microscopy of PLN cryosections dually stained for ICAM‐1 (red) and peripheral node addressin (PNAd; green). (D) To determine whether ICAM‐1 is required for the thermal enhancement of trafficking across HEVs, homing of rhodamine‐labeled splenocytes was analyzed by fluorescence microscopy 1 h after adoptive transfer to NT or WBH‐treated mice with (+) or without (–) pretreatment with anti‐ICAM‐1 blocking antibodies. Mean ± SE; 10 high‐power fields per mouse, three mice per group. * denotes p < 0.0001 versus no antibody. (E and F) To determine the role of IL‐6 in thermal augmentation of lymphocyte trafficking, the effects of WBH on ICAM‐1 expression (E) and lymphocyte homing (F) were compared in wild type and IL‐6‐deficient mice. (E) PLNs were immunostained for ICAM‐1 (red) and CCL21 (green) and analyzed by confocal microscopy. Arrowheads indicate HEVs with weak staining of ICAM‐1 or CCL21. (F) Homing of rhodamine‐labeled splenocytes in tissue cryosections from individual Il6−/− and wild‐type mice with (WBH) or without (NT) WBH treatment were quantified by fluorescence microscopy. Mean ± SW, 10 fields per mouse, three mice per group. * denotes p < 0.0001 versus NT. Coexposure to FRH enhances lymphocyte localization to HEVs through the IL‐6‐dependent expression of ICAM‐1. Reprinted in modified form with permission from references .
Figure 8. Figure 8. HSF1 structure and mechanism of activation. (A) Molecular organization of human HSF1. HR = hydrophobic region. (B) Schematic of HSF1 organization. Cytosolic HSF1 is maintained in inactive monomeric form by intramolecular interactions between HRA/B and C and heterologous binding to HSPs and other proteins. Stress (including heat) shifts the equilibrium toward trimerization, which unmasks a nuclear localization signal. The three DNA binding domains in the HSF1 trimer are oriented to produce high affinity binding to nGAAn repeats.
Figure 9. Figure 9. Model of how fever, LPS, and Hsp70 interact to cause sepsis. Proposed model of sepsis in which LPS and fever initiate a positive feedback pathway through enhanced Hsp70 expression and release and subsequent increased TLR4 activation, Hsp70 expression, and proinflammatory cytokine release. Reprinted in modified form with permission from reference .


Figure 1. Phylogenetic relationship of fever, heat shock, and innate and adaptive immunity. The modern day animals that utilize fever as a strategy for coping with infection are pictorially displayed with supporting references. The approximate phylogenetic ages of fever (600 million years) and related biological processes are shown.


Figure 2. Schematic diagram of thermoregulatory pathway including mechanism of fever regulation. See text for full discussion. To simplify, we have excluded the spinothalamocortical pathway. Abbreviations: Ach, acetycholine; BAT, brown adipose tissue thermogenesis; BBB, blood:brain barrier; DG, dorsal ganglion; DMH, dorsomedial hypothalamus; GABA, gamma‐amino butyric acid inhibitory synapse; glu, glutatergic excitatory synapse; IS, temperature‐insensitive pacemaker neuron; LPBd, dorsal subnucleus of the lateral parabrachial nucleus; LBPel, lateral external subnucleus of the LBP; MnPO, median preoptic nucleus of the hypothalamus; NA, noradrenaline; POA, preoptic area of the hypothalamus; rMR, rostral medullary raphe region; TRP, transient receptor potential channel; WS, warm‐sensing pacemaker neuron.


Figure 3. Effect of Febrile‐range hyperthermia (FRH) on pathogen clearance and host survival in mouse models of bacterial peritonitis and pneumonia. (A) The mouse FRH model in which mice in standard cages are transferred to infant incubators set at 37°C and mice then are inoculated with Klebsiella pneumoniae Caroli strain. Mice were inoculated with 100 cfu via i.p injection (B and C) or 250 cfu via i.t. instillation (D and E) and mice were housed at 23 or 37°C ambient temperature. Survival (C and E) was determined and bacterial colony counts were determined in peritoneal fluid (B) and lung homogenates (D). The p value for the survival studies is shown. The bacterial colony counts are mean ± SE of six experiments. * denotes p < 0.05 versus FRH. (F) To analyze direct effect of temperature on bacterial growth rate, 100 mL aliquots of LB medium were inoculated with 10 cfu K. pneumoniae, incubated at 37 or 39.5°C, and OD650 sequentially measured. (G) Core temperature in four mice per group housed at 23°C (NT) or 37°C (FRH). Coexposure to FRH accelerated pathogen clearance in both the pneumonia and peritonitis models but only improved survival in the peritonitis model. Reprinted in modified form with permission from references and .


Figure 4. Effect of FRH on neutrophil recruitment. Mice were exposed to >95% oxygen (A) or received 50 μg LPS via i.t. instillation (B) and were housed at 23° (NT) or 37°C (FRH) ambient temperature for the indicated time before euthanasia, lung lavage, and quantitation of lavage neutrophil content. Mean ± SE of eight (hyperoxia) or six mice per time point. * denotes p < 0.05 versus NT. (C) IL‐8‐directed trans‐alveolar migration capacity was measured in NT mice and mice exposed to FRH for the indicated time and returned to NT conditions by instilling 1 μg recombinant human IL‐8 via i.t. instillation and quantifying lung lavage neutrophil content 4 h later. Mean ± SE eight mice per group. * denotes p < 0.05 versus time 0 (prewarming). (D) To determine whether the FRH increased neutrophil migration capacity through effects on neutrophils or endothelium we performed neutrophil transfer experiments between NT and FRH. Recipient or donor mice were exposed to FRH for 24 h, donor PMNs isolated, fluorescently labeled, and injected via tail vein, and IL‐8‐directed donor PMN TAM determined by flow cytometry and manual neutrophil counts. The donor/recipient treatment is indicated on the x‐axis. Mean±SE; six mice per group. * denotes p < 0.05 versus all other groups. (E) To determine the participation of ERK and p38 MAP kinases in FRH‐augmented neutrophil migration, groups of 8 mice were untreated or treated with 2% DMSO (sham), 200 μg U0126 or 1 mg SB203580 (SB) 30 min before 16 h FRH or normothermic exposure and IL‐8‐directed PMN transalveolar migration was measured. Mean±SE. * and † denotes p < 0.05 versus normothermic and untreated mice, respectively. (F) Inflation‐fixed lungs from normothermic (NT) and 24 h‐FRH‐exposed mice 4 h after intratracheal IL‐8 instillation were stained for GR‐1 (PMNs, red) and VE‐cadherin (ECs, green), and analyzed by confocal microscopy. White and yellow arrows denote intravascular and extravasating PMNs, respectively. (G) Human Microvascular Lung Endothelial Cells (HMVEC‐Ls) were incubated at 39.5°C for indicated time or treated with 1 ng/ml TNFα for 6 h at 37°C and IL‐8 directed transendothelial migration of calcein AM‐stained human neutrophils measured over 2 h at 37°C and standardized to untreated HMVEC‐Ls. Mean±SE; four experiments. * and † denote p < 0.05 versus time‐0 and TNFα. (H) HMVEC‐Ls were untreated (Control) or pretreated for 30 min with DMSO, U0126, or SB203580 (SB), incubated for 24 h at 37°C or 39.5°C, and neutrophil transendothelial migration measured. Mean±SE; four experiments. * and † denote p < 0.05 versus 37°C and untreated 39.5°C. Coexposure to FRH increases capacity for chemokine‐directed neutrophil migration through effects on neutrophils and endothelium. Reprinted in modified form with permission from references and .


Figure 5. Effect of FRH on pulmonary vascular endothelial permeability. Mice were exposed to >95% oxygen (A) or received 50 μg LPS via i.t. instillation (B) and were housed at 23° (NT) or 37°C (FRH) ambient temperature for the indicated time before euthanasia, lung lavage, and quantitation of lavage neutrophil content. Mean ± SE of eight (hyperoxia) or six mice per time point. * and † denote p < 0.05 versus NT and time 0, respectively. (C) HMVECLs were incubated with the indicated concentration of TNFα for 6h at 37 or 39.5°C, the TNFα was removed and transendothelial flux of 10 kDa Cascade blue dextran over 30 min at 37°C was measured. (D) HMVEC‐Ls were incubated with 0.25 U/mL TNFα for 6 h at the indicated temperature and 10 kDa Cascade blue flux measured. Mean ± SE, n = 21. * and † denote changes with TNFα‐free controls and 37°C cells, respectively. (E) HMVECLs were incubated for 6 h with either 2.5 U/mL TNFα at 37°C or 0.25 U/mL TNFα at 39.5°C, the TNFα was removed, all monolayers returned to 37°C and 10 kDa Cascade blue dextran flux measured immediately and then sequentially during recovery. Mean ± SE, n = 9. * denotes p < 0.05 versus 39.5°C at time 0. (F) HMVECLs were pretreated with 10 μmol/L UO126 or p38 MAPK SB203580 for 30 min at 37°C, then incubated with 0.25 U/mL TNFα for 6 h at the indicated temperature, the TNFα was removed and 10 kDa Cascade blue dextran flux measured. Mean ± SE, n = 9. * and † denote p < 0.05 versus TNFα‐free controls and 37°C cells, respectively. (G) HMVECLs grown on chamber slides were incubated for 6 h without or with 0.25 U/mL TNFα at 37°C or 39.5°C, fixed and stained with phalloidin coupled with Alexafluor488, counterstained with DAPI, and visualized by fluorescent confocal microscopy. Intercellular gaps are noted by the arrows. (H) F‐actin staining intensity from panel G quantified and expressed relative to 37°C without TNFα. Mean±SE, n = 4. † and ‡ denote p < 0.05 versus 37°C with and without TNFα, respectively. Coexposure to FRH reversibly increases endothelial permeability. Reprinted in modified form with permission from references .


Figure 6. Effect of FRH on epithelial apoptosis. (A‐C) Mice received 50 μg LPS via i.t. instillation and were housed at 23 or 37°C ambient temperature for 48 h, the lungs were then inflation fixed and stained with hematoxalyn and eosin. A is untreated control, B and C are normothermic and FRH‐exposed mice, respectively. Arrows indicate loss of cilia and distinct nuclei. (D) Mouse MLE15 epithelial cells were incubated with indicated concentration of recombinant mouse TNFα for 24 h at 37 or 39.5°C and survival assessed by crystal violet staining and measuring absorbance at 570 nm. Mean ± SE. Survival was different with p < 0.05 by MANOVA. (E and F) MLE15 cells were incubated for indicated time at 37° or 39.5°C with or without 2 ng/mL TNFα, lysed, and immunobloted for active caspase‐3 (C3), PARP, and β‐tubulin (E) or caspase‐8 (F). Thick and thin arrows indicate full‐length and cleaved PARP and caspase‐8. Coexposure to FRH enhances LPS‐induced lung epithelial injury in vivo and accelerates TNFα‐induced apoptosis in lung epithelial cells in vitro. Reprinted in modified form with permission from references .


Figure 7. FRH enhances lymphocyte trafficking to the lymph high endothelial venule (HEV). (A) BALB/c mice were exposed to FRH (whole body hyperthermia, WBH) for 6 h and the total number of lymphocytes in peripheral blood (PB), peripheral lymph node (PLN), and spleen was quantified. Lymphocyte expression of L‐selectin and α4β7 integrin was analyzed by flow cytometry. Mean ±SE of three experiments. * and ** denote p < 0.02 and 0.03 versus control. (B) Intravital microscopy (left) of the interactions of calcein‐labeled splenocytes with the lymph node venular tree of an WBH‐treated mouse, showing the vascular structure, including the superficial epigastric artery (SEA), superficial epigastric vein (SEV) and venular branches (I‐V) in an inguinal lymph node. Right, rolling fractions and sticking fractions in normothermic (NT) and WBH‐treated mice. Mean ±SE, three mice per group. * and ** denote p < 0.0001, and p < 0.01, normothermic versus NT. (C) Expression of trafficking molecules in NT or FRH‐treated mice was analyzed by scanning confocal microscopy of PLN cryosections dually stained for ICAM‐1 (red) and peripheral node addressin (PNAd; green). (D) To determine whether ICAM‐1 is required for the thermal enhancement of trafficking across HEVs, homing of rhodamine‐labeled splenocytes was analyzed by fluorescence microscopy 1 h after adoptive transfer to NT or WBH‐treated mice with (+) or without (–) pretreatment with anti‐ICAM‐1 blocking antibodies. Mean ± SE; 10 high‐power fields per mouse, three mice per group. * denotes p < 0.0001 versus no antibody. (E and F) To determine the role of IL‐6 in thermal augmentation of lymphocyte trafficking, the effects of WBH on ICAM‐1 expression (E) and lymphocyte homing (F) were compared in wild type and IL‐6‐deficient mice. (E) PLNs were immunostained for ICAM‐1 (red) and CCL21 (green) and analyzed by confocal microscopy. Arrowheads indicate HEVs with weak staining of ICAM‐1 or CCL21. (F) Homing of rhodamine‐labeled splenocytes in tissue cryosections from individual Il6−/− and wild‐type mice with (WBH) or without (NT) WBH treatment were quantified by fluorescence microscopy. Mean ± SW, 10 fields per mouse, three mice per group. * denotes p < 0.0001 versus NT. Coexposure to FRH enhances lymphocyte localization to HEVs through the IL‐6‐dependent expression of ICAM‐1. Reprinted in modified form with permission from references .


Figure 8. HSF1 structure and mechanism of activation. (A) Molecular organization of human HSF1. HR = hydrophobic region. (B) Schematic of HSF1 organization. Cytosolic HSF1 is maintained in inactive monomeric form by intramolecular interactions between HRA/B and C and heterologous binding to HSPs and other proteins. Stress (including heat) shifts the equilibrium toward trimerization, which unmasks a nuclear localization signal. The three DNA binding domains in the HSF1 trimer are oriented to produce high affinity binding to nGAAn repeats.


Figure 9. Model of how fever, LPS, and Hsp70 interact to cause sepsis. Proposed model of sepsis in which LPS and fever initiate a positive feedback pathway through enhanced Hsp70 expression and release and subsequent increased TLR4 activation, Hsp70 expression, and proinflammatory cytokine release. Reprinted in modified form with permission from reference .
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Further Reading
 1.Nakamura K, Morrison SF. Central efferent pathways for cold‐defensive and febrile shivering. J Physiol 589: 3641, 2011.
 2.Morrison SF, Nakamura K. Central neural pathways for thermoregulation. Front Biosci 16: 74, 2011.
 3.Akerfelt M, Morimoto RI, Sistonen L. Heat shock factors: Integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11: 545, 2010.
 4.Tsan MF, Gao B. Heat shock proteins and immune system. J Leukoc Biol 85: 905, 2009.
 5.Fisher DT, Vardam TD, Muhitch JB, Evans SS. Fine‐tuning immune surveillance by fever‐range thermal stress. Immunol Res 46: 177, 2010.
 6.Hasday JD, Shah N, Mackowiack PA, Tulapurkar M, Nagarsekar A, Singh I. Fever, hyperthermia, and the lung: It's all about context and timing. Trans Am Clin Climatol Assoc 122: 34, 2011.

Further Reading

  • K. Nakamura, S. F. Morrison, Central efferent pathways for cold-defensive and febrile shivering. The Journal of physiology 589, 3641 (Jul 15, 2011).
  • S. F. Morrison, K. Nakamura, Central neural pathways for thermoregulation. Frontiers in bioscience : a journal and virtual library 16, 74 (2011).
  • M. Akerfelt, R. I. Morimoto, L. Sistonen, Heat shock factors: integrators of cell stress, development and lifespan. Nature reviews. Molecular cell biology 11, 545 (Aug, 2010).
  • M. F. Tsan, B. Gao, Heat shock proteins and immune system. Journal of Leukocyte Biology 85, 905 (Jun, 2009).
  • D. T. Fisher, T. D. Vardam, J. B. Muhitch, S. S. Evans, Fine-tuning immune surveillance by fever-range thermal stress. Immunol Res 46, 177 (Mar, 2010).
  • J. D. Hasday et al., Fever, hyperthermia, and the lung: it's all about context and timing. Trans Am Clin Climatol Assoc 122, 34 (2011).

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How to Cite

Jeffrey D. Hasday, Christopher Thompson, Ishwar S. Singh. Fever, Immunity, and Molecular Adaptations. Compr Physiol 2014, 4: 109-148. doi: 10.1002/cphy.c130019