Endotoxin priming improves clearance of Pseudomonas aeruginosa in wild-type and interleukin-10 knockout mice.
Tushar K. Varma,Megan Durham,E. D. Murphey,Weihua Cui,Zhiyu Huang,Cheng Y. Lin,Tracy Toliver-Kinsky,Edward R. Sherwood,Edward R. Sherwood +8 more
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TLDR
Induction of LPS tolerance enhanced systemic clearance of Pseudomonas aeruginosa and that this effect was augmented by neutralization of IL-10, which reversed the endotoxin-tolerant state.Abstract:
Endotoxin (lipopolysaccharide [LPS]) tolerance is an altered state of immunity caused by prior exposure to LPS, in which production of many cytokines, including gamma interferon (IFN-γ) and interleukin-12 (IL-12), are reduced but secretion of the anti-inflammatory cytokine IL-10 is increased in response to a subsequent LPS challenge. This pattern of cytokine production is also characteristic of postinflammatory immunosuppression. Therefore, we hypothesized that LPS-primed mice would exhibit an impaired ability to respond to systemic infection with the opportunistic pathogen Pseudomonas aeruginosa. We further hypothesized that depletion of IL-10 would reverse the endotoxin-tolerant state. To test this hypothesis, systemic clearance of Pseudomonas aeruginosa was measured for LPS-primed wild-type and IL-10-deficient mice. LPS-primed wild-type mice exhibited significant suppression of LPS-induced IFN-γ and IL-12 but increased IL-10 production in blood and spleen compared to levels exhibited by saline-primed wild-type mice. The suppressed production of IFN-γ and IL-12 caused by LPS priming was ablated in the spleens, but not blood, of IL-10 knockout mice. LPS-primed wild-type mice cleared Pseudomonas aeruginosa from lungs and blood more effectively than saline-primed mice. LPS-primed IL-10-deficient mice were particularly efficient in clearing Pseudomonas aeruginosa after systemic challenge. These studies show that induction of LPS tolerance enhanced systemic clearance of Pseudomonas aeruginosa and that this effect was augmented by neutralization of IL-10.read more
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Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis.
Suhas G. Kallapur,Alan H. Jobe,Molly K. Ball,Ilias Nitsos,Timothy J. M. Moss,Noah H. Hillman,John P. Newnham,Boris W. Kramer +7 more
TL;DR: Results are consistent with the novel finding of endotoxin tolerance in preterm fetal lungs exposed to intra-amniotic LPS, and have implications for preterm infants exposed to chorioamnionitis for both responses to lung injury and postnatal nosocomial infections.
Journal ArticleDOI
T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response
Xiaomei Yang,Xingwei Jiang,Guojiang Chen,Yan Xiao,Shaoxia Geng,Kang Chunyan,Tingting Zhou,Yurong Li,Xiaoqin Guo,He Xiao,Chunmei Hou,Renxi Wang,Zhou Lin,Xinying Li,Jiannan Feng,Yuanfang Ma,Beifen Shen,Yan Li,Gencheng Han +18 more
TL;DR: It is found that downregulation and/or blockade of T cell Ig and mucin domain protein 3 (Tim-3), a negative immune regulator, correlated with severity of sepsis, suggesting that Tim-3 plays important roles in maintaining the homeostasis of sePSis in both humans and a mouse model.
Journal ArticleDOI
Induction of endotoxin tolerance enhances bacterial clearance and survival in murine polymicrobial sepsis
Derek S. Wheeler,Patrick Lahni,Alvin Denenberg,Sue E. Poynter,Sue E. Poynter,Hector R. Wong,Hector R. Wong,James A. Cook,Basilia Zingarelli,Basilia Zingarelli +9 more
TL;DR: It is concluded that endotoxin tolerance significantly attenuates the host inflammatory response, augments bacterial clearance, and improves survival in this murine model of polymicrobial sepsis.
Journal ArticleDOI
The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants.
TL;DR: The potency of lipid A analogs as immunoadjuvants represent an attractive family of immunomodulators and numerous laboratories are actively working to identify and develop new lipid A mimetics and to optimize their efficacy and safety.
Journal ArticleDOI
Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-β production
TL;DR: This study has shown that, whilst NF‐κB activation and production of TNF‐α and interleukin‐12 by murine RAW264.7 and J774.2 cells in response to stimulation by TLR4, ‐5, ‑7 or ‐9, was reduced by prior stimulation with TLR3, the response toTLR3 stimulation was not diminished by prior TLR ligand exposure.
References
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Journal ArticleDOI
Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions
TL;DR: It is found that immature monocyte-derived DCs released low but sizeable amounts of IL-10, and addition of an anti-IL-10-neutralizing Ab to immature DCs as well as to soluble CD40 ligand- or LPS-maturing DCs led to enhanced expression of surface CD83, CD80, CD86, and MHC molecules and markedly augmented release of TNF-α and IL-12, but diminished IL- 10 mRNA expression.
Journal ArticleDOI
Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.
Daniel J. Berg,Ralf Kühn,Klaus Rajewsky,Werner Müller,Satish Menon,Natalie J. Davidson,Gabriele Grunig,Donna M. Rennick +7 more
TL;DR: Results show that IL-10 is a critical component of the host's natural defense against the development of pathologic responses to LPS although it is not responsible for LPS-induced tolerance.
Journal ArticleDOI
Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection.
TL;DR: Peripheral blood mononuclear cells from burn and trauma patients produced less IFN-τ, the index cytokine of Th-1 cells, than PBMCs from healthy individuals 1 to 14 days after burn injury (SE = 77.6 ± 16 pg/mL patients vs. 672.0 ± 22.7 pg/ mL controls, p < 0.05).
Journal ArticleDOI
Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta.
Felix Randow,Uta Syrbe,Christian Meisel,Dietmar Krausch,H. Zuckermann,Cornelia Platzer,Hans-Dieter Volk +6 more
TL;DR: In vitro induced LPS tolerance looks like the ex vivo LPS hyporesponsiveness of monocytes from septic patients with fatal outcome: downregulation of LPS-induced TNF-alpha and IL-10 production but not of IL-1RA secretion.
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Molecular mechanisms of endotoxin tolerance
Hongkuan Fan,James A. Cook +1 more
TL;DR: Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.