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The Journal of Immunology, 2002, 169: 2823-2827.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Myeloid Differentiation Factor 88 Deficiency Improves Resistance Against Sepsis Caused by Polymicrobial Infection1

Heike Weighardt*, Simone Kaiser-Moore*, Ramunas M. Vabulas{dagger}, Carsten J. Kirschning{dagger}, Hermann Wagner{dagger} and Bernhard Holzmann2,*

* Department of Surgery, Klinikum rechts der Isar, and {dagger} Institute of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Munich, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Toll-like receptors (TLRs) are important for the activation of innate immune cells upon encounter of microbial pathogens. The present study investigated the potential roles of TLR2, TLR4, and the signaling protein myeloid differentiation factor 88 (MyD88) in polymicrobial septic peritonitis. Whereas both TLR2 and TLR4 were dispensable for host defense against septic peritonitis, MyD88-deficient mice were protected in this infection model. Recruitment of neutrophils to the septic focus and bacterial clearance were normal in MyD88-deficient mice. In contrast, the systemic inflammatory response was strongly attenuated in the absence of MyD88. Surprisingly, MyD88 deficiency did not alter cytokine and chemokine production in spleen, but markedly reduced the inflammatory response in liver and lung. Production of monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1{alpha} was entirely independent of MyD88. These results imply a central role of MyD88 for the systemic immune pathology of polymicrobial sepsis and show that cytokine production in spleen and induction of certain chemokines are MyD88 independent.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Toll-like receptors (TLRs)3 are a family of germline-encoded receptors of innate immunity that recognize conserved molecular patterns of microbial pathogens (1, 2). Ten members of the mammalian TLR family have been reported, with each TLR showing a distinct recognition profile for molecular constituents of microbes (1, 3). Several reports have identified the TLR4/MD-2 complex as the major signaling receptor for LPS in mammals (4, 5, 6, 7). The ligand specificity and signal transduction capacity of TLR2 is influenced by heterodimerization with other TLRs, such as TLR1 and TLR6, thereby providing a possible explanation for the broad specificity of TLR2 for multiple microbial components (3, 8, 9, 10, 11, 12).

Myeloid differentiation factor 88 (MyD88) has been identified as a central adapter protein for signal transduction of TLRs and the IL-1R family (13, 14). MyD88 interacts with TLRs and recruits IL-1R-associated kinases to the receptors (15, 16, 17). Subsequently, IL-1R-associated kinases associate with the TNFR-activated factor 6, which leads to the activation of signaling pathways such as mitogen-activated protein kinases and NF-{kappa}B, as well as the induction of cytokines. Macrophages from MyD88 knockout mice do not produce TNF in response to a large number of bacterial cell wall components, emphasizing the central role of MyD88 for integrating signals from multiple TLRs (18). However, exposure of MyD88-deficient macrophages with LPS results in the delayed activation of NF-{kappa}B and mitogen-activated protein kinases, suggesting the existence of MyD88-independent signaling pathways (19, 20, 21, 22).

An important question of TLR immunobiology is their contribution to the multifaceted cellular responses during infection with microbial pathogens in vivo. We addressed this issue by analyzing the roles of TLR2, TLR4, and MyD88 for host defense against sepsis caused by polymicrobial infection. The genetic deficiency of MyD88, but not of TLR2 and TLR4, protected mice against septic peritonitis, indicating that effective antibacterial immune responses may occur in the absence of MyD88. Interestingly, the local neutrophil response and the production of immune mediators in peripheral organs were partially MyD88 independent.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mouse strains and colon ascendens stent peritonitis (CASP) model of polymicrobial septic peritonitis

MyD88-deficient mice backcrossed eight times to the C57BL/6 background were kindly provided by Dr. S. Akira (Osaka, Japan) (13). TLR2-deficient mice were a kind gift of Tularik (South San Francisco, CA) (23). Control C57BL/6 mice, C3H/HeN (TLR4+/+) mice, and TLR4-deficient C3H/HeJ (TLR4d/d) mice were purchased from Harlan Winkelmann (Borchem, Germany). TLR2-deficient mice were backcrossed five times with the C3H/HeJ strain to obtain mice doubly deficient for TLR2 and TLR4 (TLR2-/-TLR4d/d). Mice at 8–12 wk of age were used for all experiments. The CASP procedure used for induction of septic peritonitis was described in detail previously (24).

Bacterial counts and peritoneal neutrophil accumulation

Mice were sacrificed before or 12 h after CASP and peritoneal lavage fluid was collected. Serial dilutions of lavage fluids were plated on blood agar plates. CFU were counted after incubation at 37°C for 24 h and calculated as CFU per whole peritoneal cavity. In addition, peritoneal lavage cells were counted and differentiated by staining with Abs against Mac-1 (M1/70) and Ly-6G/Gr-1 (RB6-8C5) using appropriate isotype-matched controls (all from BD PharMingen, San Diego, CA).

Analysis of cytokine and chemokine production

Peripheral blood, spleen, liver, and lung were collected before or 12 h after CASP. Peripheral organs were snap-frozen in liquid nitrogen and homogenized after thawing in 1 ml PBS containing complete protease inhibitors (Roche Diagnostics, Mannheim, Germany). Organ extracts were centrifuged (6000 x g for 20 min at 4°C) and mediator concentrations were measured in supernatants by ELISA specific for TNF, IL-10, IL-12, macrophage-inflammatory protein (MIP)-1{alpha}, MIP-2, cytokine-induced neutrophil chemoattractant (KC), or monocyte chemoattractant protein (MCP)-1 (all from R&D Systems, Minneapolis, MN). Immune mediator levels in peripheral organs were normalized against the protein concentration in each organ extract as determined by the bicinchoninic acid kit (Pierce, Rockford, IL).

Statistical analysis

Statistical analysis of the data was performed using the Mann-Whitney U test or the Student t test where appropriate. Survival data were analyzed by log-rank test. All data are presented as mean ± SEM. The level of significance was p < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
MyD88-deficient mice are protected from the lethal effects of polymicrobial septic peritonitis

Mice deficient for TLR2, TLR4, or MyD88 are highly susceptible to monomicrobial infection with bacterial or viral pathogens (25, 26, 27, 28, 29). To elucidate the potential role of TLRs and MyD88 for the immune defense against polymicrobial infection, we analyzed gene-deficient mice in a model of acute septic peritonitis. As demonstrated in Fig. 1Go genetic deficiencies in TLR2 or TLR4 did not significantly alter survival of polymicrobial septic peritonitis. Survival of mice deficient for both TLR2 and TLR4 (TLR2-/-TLR4d/d) also did not significantly differ from that of controls. In contrast, survival of MyD88-deficient mice was significantly improved when compared with wild-type controls (Fig. 1Go). The overall survival rate of MyD88 knockout mice was 64.3% as compared with 21.4% for wild-type mice.



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  		FIGURE 1. Improved survival of acute polymicrobial peritonitis in MyD88-deficient mice. Gene-deficient (TLR2-/-, TLR4d/d, TLR2-/-TLR4d/d, and MyD88-/-) and control mice were subjected to the CASP procedure and survival was monitored. In each experimental series, gene-deficient and control mice were used that were matched for gender and age. Data were pooled from two to three independent experiments for each mouse strain, with each experiment demonstrating similar results.

 
Bacterial clearance and peritoneal neutrophil recruitment are not altered by MyD88 deficiency

To further explore host defense mechanisms in MyD88-deficient mice, bacterial counts were determined in the septic focus. As depicted in Fig. 2GoA, MyD88 knockout and control mice exhibited similar bacterial counts in peritoneal cavity (p = 0.224), indicating that bacterial clearance in polymicrobial septic peritonitis is not impaired by MyD88 deficiency.



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  		FIGURE 2. Normal bacterial clearance and peritoneal neutrophil recruitment in MyD88-deficient mice. A, Peritoneal lavage fluid was obtained 12 h after CASP from MyD88-deficient (-/-) or control mice (+/+) and total bacterial counts were determined. Results are derived from four independent mice per group. There was no significant difference between the bacterial counts of knockout and wild-type mice (p = 0.224). B, Peritoneal cells were harvested from MyD88-deficient (-/-) or control mice (+/+) immediately before CASP (0 h) or 12 h thereafter. Neutrophils were identified by high expression of Gr-1 and Mac-1. Neutrophil numbers were determined from four independent mice per group and time point. #, p < 0.05 (MyD88-/- at 0 vs 12 h); §, p < 0.05 (C57BL/6 at 0 vs 12 h).

 
The innate immune defense against septic peritonitis is critically dependent on effector neutrophils. Therefore, it was interesting to observe that the absolute numbers of neutrophils accumulating in the infected peritoneal cavity were comparable in MyD88-deficient and control mice (Fig. 2GoB). These results suggest that neutrophil recruitment to the primary site of infection is MyD88 independent.

Distinct effects of MyD88 deficiency on local and systemic cytokine production during polymicrobial septic peritonitis

High systemic levels of inflammatory cytokines may contribute to organ injury and shock during sepsis. To elucidate potential mechanisms of protection in MyD88-deficient mice, we investigated serum cytokine levels 12 h after induction of septic peritonitis. The results in Fig. 3GoA show that serum concentrations of TNF, IL-12, and IL-10 were significantly increased in septic as compared with nonseptic control mice but remained low in septic MyD88-deficient mice. Production of IL-10 in response to septic peritonitis was also substantially impaired in MyD88 knockout mice, although a significant release of small amounts was detected (Fig. 3GoA). Interestingly, the systemic inflammatory response as measured by serum KC levels was not altered in mice deficient for either TLR2 or TLR4 but was weakly reduced in TLR2/TLR4 double-deficient mice. In contrast, systemic KC levels were close to baseline in MyD88-deficient mice (Fig. 3GoB).



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  		FIGURE 3. MyD88 deficiency attenuates serum cytokine levels during septic peritonitis. A, Serum samples were obtained before (0 h) and 12 h after CASP from MyD88 knockout (-/-) and control mice (+/+), and cytokine levels were determined. Results are derived from four mice per group and time point. *, p < 0.05 (MyD88-/- vs C57BL/6); #, p < 0.05 (MyD88-/- at 0 vs 12 h); §, p < 0.05 (C57BL/6 at 0 vs 12 h). B, Serum samples were collected 12 h after CASP from the mouse strains indicated and KC levels were determined. *, p < 0.001 (MyD88-/- vs C57BL/6); #, p < 0.05 (MyD88-/- vs TLR2-/-TLR4d/d); §, p < 0.05 (TLR2-/-TLR4d/d vs C3H/HeN).

 
Next, we examined the role of MyD88 for the cytokine response in different anatomic compartments by determining the concentrations of TNF, IL-12, and IL-10 in whole-organ protein extracts (Fig. 4Go). In septic control mice, TNF and IL-10 levels were elevated at comparable levels both in liver, lung, and spleen, whereas significant up-regulation of IL-12 was observed only in liver. However, in MyD88 knockout mice the regulation of cytokine production showed marked differences in the organ compartments tested. Whereas the sepsis-induced increase of TNF and IL-10 levels in liver and lung was almost completely abrogated by MyD88 deficiency, production of these cytokines in spleen appeared not to be affected in MyD88-deficient mice (Fig. 4Go). These results suggest a distinct regulation of cytokine production in spleen.



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  		FIGURE 4. Diminished cytokine levels in peripheral organs of MyD88-deficient mice. Lung, liver, and spleen were removed from MyD88 knockout (-/-) and control mice (+/+) mice before (0 h) or 12 h after CASP. Organs were homogenized and protein extracts were prepared. Cytokine concentrations determined by ELISA were normalized against the total protein concentration. Results are derived from four mice per group and time point. *, p < 0.05 (MyD88-/- vs C57BL/6); #, p < 0.05 (MyD88-/- at 0 vs 12 h); §, p < 0.05 (C57BL/6 at 0 vs 12 h).

 
Chemokines play a pivotal role in the innate immune response to experimental sepsis. Therefore, we measured chemokine production in protein extracts of liver, lung, and spleen. The results in Fig. 5Go demonstrate that, in all organs tested, sepsis-induced production of the CC chemokines MCP-1 and MIP-1{alpha} did not significantly differ between MyD88 knockout and control mice, implying that the induction of these chemokines is largely independent of MyD88. In contrast, the CXC chemokines KC and MIP-2 were significantly reduced in liver and lung of MyD88-deficient mice as compared with wild-type mice. Consistent with the results of cytokine analysis (Fig. 4), production of KC and MIP-2 was also not significantly altered in spleens of septic MyD88-deficient mice (Fig. 5Go).



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  		FIGURE 5. Differential effects of MyD88 deficiency on chemokine levels during septic peritonitis. Lung, liver, and spleen were removed from MyD88 knockout (-/-) and control mice (+/+) mice before (0 h) or 12 h after CASP. Organs were homogenized and protein extracts were prepared. Chemokine concentrations were measured by ELISA and normalized against the total protein concentration. Results are derived from four mice per group and time point. *, p < 0.05 (MyD88-/- vs C57BL/6); #, p < 0.05 (MyD88-/- at 0 vs 12 h); §, p < 0.05 (C57BL/6 at 0 vs 12 h).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present report reveals new insights into the role of MyD88 for the complex immune pathology of polymicrobial sepsis. We demonstrate that MyD88 deficiency renders mice more resistant to the lethal effects of sepsis after polymicrobial peritonitis. Although previous reports have shown that MyD88-deficient mice are highly susceptible to monomicrobial infection with Staphylococcus aureus (26) or Toxoplasma gondii (30), the infection models applied may provide an explanation for these different observations. MyD88-dependent TLR signaling appears to be required for activation of protective immune responses during infection with low amounts of a single bacterial pathogen. In contrast, acute polymicrobial sepsis may expose innate immune cells to large amounts of diverse microbial components. Under these conditions, MyD88-dependent signaling may exceed the levels required for efficient host defense and may instead contribute to the detrimental hyperinflammation. However, depending on the type and dosage of pathogen applied, it is conceivable that MyD88-deficient mice may also exhibit increased resistance in certain models of monomicrobial sepsis. Therefore, prevention of an uncontrolled inflammatory response may contribute, at least in part, to the protective effects of MyD88 deficiency in polymicrobial sepsis. Our results showing that mice deficient for MyD88, but not TLR2 and/or TLR4, exhibit markedly reduced systemic cytokine levels during polymicrobial sepsis support this view.

MyD88-deficient mice have been reported to resist hyperinflammation and lethal shock after administration of high-dose LPS (14). The sepsis model applied in this study clearly differs from such toxic shock models by challenging mice with a large number of diverse bacterial pathogens. As a consequence, beneficial effects for the outcome of sepsis caused by polymicrobial infection may not only require attenuation of the systemic hyperinflammatory response but may also depend on the activation of efficient antibacterial defense mechanisms. Our results showing efficient bacterial clearance in MyD88 knockout mice are consistent with this notion. It appears likely that the intact bacterial clearance in septic MyD88-deficient mice may be explained, at least in part, by their unaltered peritoneal neutrophil accumulation.

The results of the present report also reveal new information about the role of MyD88 for the production of inflammatory mediators during infectious processes in vivo. We provide evidence for the existence of MyD88-dependent as well as MyD88-independent pathways of cytokine and chemokine production during polymicrobial septic peritonitis. The sepsis-induced up-regulation of cytokines and chemokines was found to be normal in spleen of MyD88 knockout mice but was almost completely abolished in lung and liver. These results indicate that the requirement of MyD88 for the local production of immune mediators during polymicrobial sepsis is dependent on the anatomical compartment involved. Recent work has identified a splice variant of MyD88 that acts as a dominant negative inhibitor of NF-{kappa}B activation by IL-1 and LPS and is the predominant form of MyD88 in spleen but not in other organs (31). Together, these observations suggest that mainly MyD88-independent pathway(s) may mediate cytokine production in spleen.

In addition, we have observed that both wild-type and MyD88-deficient mice challenged by septic peritonitis exhibited a comparable production of the CC chemokines MCP-1 and MIP-1{alpha} in all organs tested, whereas production of CXC chemokines (MIP-2, KC) and cytokines (TNF, IL-12, IL-10) was strongly impaired in liver and lung, but not spleen, of MyD88-deficient mice. Thus, these results further suggest that, during polymicrobial sepsis, distinct subsets of immune mediators can be defined that are produced either in a MyD88-independent or a MyD88-dependent manner. These results are also consistent with previous findings indicating that production of inflammatory proteins including IFN-{beta}, IFN-{gamma}-inducible protein-10, MCP-5, and inducible NO synthase by macrophages in vitro does not require MyD88 (21, 22).

The present study investigated not only the role of the common signaling adapter protein MyD88 but also the role of TLR2 and TLR4 in polymicrobial sepsis. We found that TLR2 and TLR4, either as individual receptors or in conjunction, are dispensable for the host defense against septic peritonitis. Moreover, combined deficiency of both TLR2 and TLR4 had only minor effects on the systemic inflammatory response as measured by serum KC levels. These findings suggest that other microbial agonists such as flagellin or bacterial DNA may also play a pathogenic role. Numerous TLRs may be triggered during polymicrobial sepsis, thereby rendering individual TLRs dispensable for immune activation and stimulation of host defense mechanisms. In addition, innate immune receptors other than TLRs may be activated.

In summary, the role of TLRs for host defense during infection was studied in a model of polymicrobial sepsis. We show that the genetic deficiency of MyD88, but not of TLR2 and TLR4, results in a significant survival benefit. Importantly, the local production of immune mediators in peripheral organs was found to be partially MyD88 independent. The molecular characterization of these MyD88-independent pathways may provide new insights into the regulation of the innate immune response to severe infection.


   Acknowledgments
 
We thank Dr. Shizuo Akira for providing the MyD88-deficient mouse strain.


   Footnotes
 
1 This work was supported by the Deutsche Forschungsgemeinschaft through SFB 576 (project A7) and the Kommission für Klinische Forschung, Klinikum rechts der Isar. Back

2 Address correspondence and reprint requests to Dr. Bernhard Holzmann, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany. E-mail address: holzmann{at}nt1.chir.med.tu-muenchen.de Back

3 Abbreviations used in this paper: TLR, Toll-like receptor; CASP, colon ascendens stent peritonitis; MCP, monocyte chemoattractant protein; MyD88, myeloid differentiation factor 88; MIP, macrophage-inflammatory protein; KC, cytokine-induced neutrophil chemoattractant. Back

Received for publication June 10, 2002. Accepted for publication July 26, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kopp, E. B., R. Medzhitov. 1999. The Toll-receptor family and control of innate immunity. Curr. Opin. Immunol. 11:13.[Medline]
  2. Medzhitov, R., Jr C. A. Janeway. 2000. Innate immunity. N. Engl. J. Med. 343:338.[Free Full Text]
  3. Akira, S., K. Takeda, T. Kaisho. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2:675.[Medline]
  4. Hoshino, K., O. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Takeda, S. Akira. 1999. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162:3749.[Abstract/Free Full Text]
  5. Poltorak, A., X. He, I. Smirnova, M.-Y. Liu, C. van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, et al 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085.[Abstract/Free Full Text]
  6. Qureshi, S. T., L. Lariviére, G. Leveque, S. Clermont, K. J. Moore, P. Gros, D. Malo. 1999. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189:615.[Abstract/Free Full Text]
  7. Shimazu, R., S. Akashi, H. Ogata, Y. Nagai, K. Fukudome, K. Miyake, M. Kimoto. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189:1777.[Abstract/Free Full Text]
  8. Bulut, Y., E. Faure, L. Thomas, O. Equils, M. Arditi. 2001. Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J. Immunol. 167:987.[Abstract/Free Full Text]
  9. Hajjar, A. M., D. S. O’Mahony, A. Ozinsky, D. M. Underhill, A. Aderem, S. J. Klebanoff, C. B. Wilson. 2001. Functional interactions between Toll-like receptor (TLR)2 and TLR1 or TLR6 in response to phenol-soluble modulin. J. Immunol. 166:15.[Abstract/Free Full Text]
  10. Ozinsky, A., D. M. Underhill, J. D. Fontenot, A. M. Hajjar, K. D. Smith, C. B. Wilson, L. Schroeder, A. Aderem. 2000. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl. Acad. Sci. USA 97:13766.[Abstract/Free Full Text]
  11. Takeuchi, O., T. Kawai, P. F. Mühlradt, M. Morr, J. D. Radolf, A. Zychlinsky, K. Takeda, S. Akira. 2001. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13:993.[Abstract/Free Full Text]
  12. Wyllie, D. H., E. Kiss-Toth, A. Visintin, S. C. Smith, S. Boussouf, D. M. Segal, G. W. Duff, S. K. Dower. 2000. Evidence for an accessory protein function for Toll-like receptor 1 in antibacterial responses. J. Immunol. 165:7125.[Abstract/Free Full Text]
  13. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143.[Medline]
  14. Kawai, T., O. Adachi, T. Ogawa, K. Takeda, S. Akira. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115.[Medline]
  15. Muzio, M., J. Ni, P. Feng, V. M. Dixit. 1997. IRAK (pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278:1612.[Abstract/Free Full Text]
  16. Wesche, H., W. J. Henzel, W. Shillinglaw, S. Li, Z. Cao. 1997. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837.[Medline]
  17. Medzhitov, R., P. Preston-Hurlburt, E. Kopp, A. Stadlen, C. Chen, S. Ghosh, C. A. Janeway. 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2:253.[Medline]
  18. Takeuchi, O., K. Takeda, K. Hoshino, O. Adachi, T. Ogawa, S. Akira. 2000. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int. Immunol. 12:113.[Abstract/Free Full Text]
  19. Fitzgerald, K. A., E. M. Palsson-McDermott, A. G. Bowie, C. A. Jefferies, A. S. Mansell, G. Brady, E. Brint, A. Dunne, P. Gray, M. T. Harte, et al 2001. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78.[Medline]
  20. Horn, T., G. M. Barton, R. Medzhitov. 2001. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2:835.[Medline]
  21. Toshchakov, V., B. W. Jones, P.-Y. Perera, K. Thomas, M. J. Cody, S. Zhang, B. R. G. Williams, J. Major, T. A. Hamilton, M. J. Fenton, S. N. Vogel. 2002. TLR4, but not TLR2, mediates IFN-{beta}-induced STAT1 {alpha}/{beta}-dependent gene expression in macrophages. Nat. Immunol. 3:392.[Medline]
  22. Kawai, T., O. Takeuchi, T. Fujita, J. Inoue, P. F. Mühlradt, S. Sato, K. Hoshino, S. Akira. 2001. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167:5887.[Abstract/Free Full Text]
  23. Werts, C., R. I. Tapping, J. C. Mathison, T.-H. Chuang, V. Kravchenko, I. Saint Girons, D. A. Haake, P. J. Godowski, F. Hayashi, A. Ozinsky, et al 2001. Leptospiral lipopolysaccharide activates cells through a TLR-2 dependent mechanism. Nat. Immunol. 2:346.[Medline]
  24. Zantl, N., A. Uebe, B. Neumann, H. Wagner, J. R. Siewert, B. Holzmann, C. D. Heidecke, K. Pfeffer. 1998. Essential role of {gamma}-interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect. Immun. 66:2300.[Abstract/Free Full Text]
  25. O’Brien, A. D., D. L. Rosenstreich, I. Scher, G. H. Campbell, R. P. MacDermott, S. B. Formal. 1980. Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J. Immunol. 124:20.[Medline]
  26. Takeuchi, O., K. Hoshino, S. Akira. 2000. TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immunol. 165:5392.[Abstract/Free Full Text]
  27. Kurt-Jones, E. A., L. Popova, L. Kwinn, L. M. Haynes, L. P. Jones, R. A. Tripp, E. E. Walsh, M. W. Freeman, D. T. Golenbock. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1:398.[Medline]
  28. Wang, X., C. Moser, J.-P. Louboutin, E. S. Lysenko, D. J. Weiner, J. N. Weiser, J. M. Wilson. 2002. Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. J. Immunol. 168:810.[Abstract/Free Full Text]
  29. Wooten, R. M., Y. Ma, R. A. Yoder, J. P. Brown, J. H. Weis, J. F. Zachary, C. J. Kirschning, J. J. Weis. 2002. Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J. Immunol. 168:348.[Abstract/Free Full Text]
  30. Scanga, C. A., J. Aliberti, D. Jankovic, F. Tilloy, S. Bennouna, E. Y. Denkers, R. Medzhitov, A. Sher. 2002. MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J. Immunol. 168:5997.[Abstract/Free Full Text]
  31. Janssens, S., K. Burns, J. Tschopp, R. Beyaert. 2002. Regulation of interleukin-1- and lipopolysaccharide-induced NF-{kappa}B activation by alternative splicing of MyD88. Curr. Biol. 12:467.[Medline]



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Home page
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G. Plitas, B. M. Burt, H. M. Nguyen, Z. M. Bamboat, and R. P. DeMatteo
Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis
J. Exp. Med., June 9, 2008; 205(6): 1277 - 1283.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. C. Nance, A.-K. Yi, F. C. Re, and E. A. Fitzpatrick
MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis
J. Leukoc. Biol., May 1, 2008; 83(5): 1207 - 1217.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
H. Yasuda, A. Leelahavanichkul, S. Tsunoda, J. W. Dear, Y. Takahashi, S. Ito, X. Hu, H. Zhou, K. Doi, R. Childs, et al.
Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury
Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1050 - F1058.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
P. C. Dagher and D. P. Basile
An expanding role of Toll-like receptors in sepsis-induced acute kidney injury
Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1048 - F1049.
[Full Text] [PDF]

Home page
 Innate ImmunityHome page
J. Dagvadorj, Y. Naiki, G. Tumurkhuu, F. Hassan, S. Islam, N. Koide, I. Mori, T. Yoshida, and T. Yokochi
Interleukin-10 inhibits tumor necrosis factor-{alpha} production in lipopolysaccharide-stimulated RAW 264.7 cells through reduced MyD88 expression
Innate Immunity, April 1, 2008; 14(2): 109 - 115.
[Abstract] [PDF]

Home page
 J. Leukoc. Biol.Home page
O. M. Peck-Palmer, J. Unsinger, K. C. Chang, C. G. Davis, J. E. McDunn, and R. S. Hotchkiss
Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival
J. Leukoc. Biol., April 1, 2008; 83(4): 1009 - 1018.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Leendertse, R. J. L. Willems, I. A. J. Giebelen, P. S. van den Pangaart, W. J. Wiersinga, A. F. de Vos, S. Florquin, M. J. M. Bonten, and T. van der Poll
TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in Murine Enterococcus faecium Peritonitis
J. Immunol., April 1, 2008; 180(7): 4865 - 4874.
[Abstract] [Full Text] [PDF]

Home page
 J ANIM SCIHome page
R. A. Frost and C. H. Lang
Regulation of muscle growth by pathogen-associated molecules
J Anim Sci, April 1, 2008; 86(14_suppl): E84 - E93.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
B. Daubeuf, J. Mathison, S. Spiller, S. Hugues, S. Herren, W. Ferlin, M. Kosco-Vilbois, H. Wagner, C. J. Kirschning, R. Ulevitch, et al.
TLR4/MD-2 Monoclonal Antibody Therapy Affords Protection in Experimental Models of Septic Shock
J. Immunol., November 1, 2007; 179(9): 6107 - 6114.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
N. Rodriguez, J. Mages, H. Dietrich, N. Wantia, H. Wagner, R. Lang, and T. Miethke
MyD88-dependent changes in the pulmonary transcriptome after infection with Chlamydia pneumoniae
Physiol Genomics, July 18, 2007; 30(2): 134 - 145.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. R. Power, B. Li, M. Yamamoto, S. Akira, and T.-J. Lin
A Role of Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing IFN-beta in the Host Response to Pseudomonas aeruginosa Lung Infection in Mice
J. Immunol., March 1, 2007; 178(5): 3170 - 3176.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Riccioli, D. Starace, R. Galli, A. Fuso, S. Scarpa, F. Palombi, P. De Cesaris, E. Ziparo, and A. Filippini
Sertoli Cells Initiate Testicular Innate Immune Responses through TLR Activation
J. Immunol., November 15, 2006; 177(10): 7122 - 7130.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
H. Weighardt, S. Kaiser-Moore, S. Schlautkotter, T. Rossmann-Bloeck, U. Schleicher, C. Bogdan, and B. Holzmann
Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis
J. Immunol., October 15, 2006; 177(8): 5623 - 5630.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
H. Weighardt, J. Mages, G. Jusek, S. Kaiser-Moore, R. Lang, and B. Holzmann
Organ-Specific Role of MyD88 for Gene Regulation during Polymicrobial Peritonitis.
Infect. Immun., June 1, 2006; 74(6): 3618 - 3632.
[Abstract] [Full Text] [PDF]

Home page
 Arch SurgHome page
L. Romics Jr, G. Szabo, J. C. Coffey, J. H. Wang, and H. P. Redmond
The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases
Arch Surg, June 1, 2006; 141(6): 595 - 601.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
J. Katz, P. Zhang, M. Martin, S. N. Vogel, and S. M. Michalek
Toll-Like Receptor 2 Is Required for Inflammatory Responses to Francisella tularensis LVS.
Infect. Immun., May 1, 2006; 74(5): 2809 - 2816.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. A. Vickers, H. Zhang, M. J. Graham, K. M. Lemonidis, C. Zhao, and N. M. Dean
Modification of MyD88 mRNA Splicing and Inhibition of IL-1beta Signaling in Cell Culture and in Mice with a 2'-O-Methoxyethyl-Modified Oligonucleotide
J. Immunol., March 15, 2006; 176(6): 3652 - 3661.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
D. Conte, M. Holcik, C. A. Lefebvre, E. LaCasse, D. J. Picketts, K. E. Wright, and R. G. Korneluk
Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage Survival
Mol. Cell. Biol., January 15, 2006; 26(2): 699 - 708.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
Y. Sang, B. Ramanathan, C. R. Ross, and F. Blecha
Gene Silencing and Overexpression of Porcine Peptidoglycan Recognition Protein Long Isoforms: Involvement in {beta}-Defensin-1 Expression
Infect. Immun., November 1, 2005; 73(11): 7133 - 7141.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
F. Geisler, H. Algul, M. Riemann, and R. M. Schmid
Questioning Current Concepts in Acute Pancreatitis: Endotoxin Contamination of Porcine Pancreatic Elastase Is Responsible for Experimental Pancreatitis-Associated Distant Organ Failure
J. Immunol., May 15, 2005; 174(10): 6431 - 6439.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
N. Rodriguez, F. Fend, L. Jennen, M. Schiemann, N. Wantia, C. U. P. da Costa, S. Durr, U. Heinzmann, H. Wagner, and T. Miethke
Polymorphonuclear Neutrophils Improve Replication of Chlamydia pneumoniae In Vivo upon MyD88-Dependent Attraction
J. Immunol., April 15, 2005; 174(8): 4836 - 4844.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
H. Bjorkbacka, K. A. Fitzgerald, F. Huet, X. Li, J. A. Gregory, M. A. Lee, C. M. Ordija, N. E. Dowley, D. T. Golenbock, and M. W. Freeman
The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades
Physiol Genomics, February 7, 2005; 19(3): 319 - 330.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. R. Power, Y. Peng, E. Maydanski, J. S. Marshall, and T.-J. Lin
The Development of Early Host Response to Pseudomonas aeruginosa Lung Infection Is Critically Dependent on Myeloid Differentiation Factor 88 in Mice
J. Biol. Chem., November 19, 2004; 279(47): 49315 - 49322.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
P. A. Pioli, E. Amiel, T. M. Schaefer, J. E. Connolly, C. R. Wira, and P. M. Guyre
Differential Expression of Toll-Like Receptors 2 and 4 in Tissues of the Human Female Reproductive Tract
Infect. Immun., October 1, 2004; 72(10): 5799 - 5806.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
U. Koedel, T. Rupprecht, B. Angele, J. Heesemann, H. Wagner, H.-W. Pfister, and C. J. Kirschning
MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS
Brain, June 1, 2004; 127(6): 1437 - 1445.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
G. Mancuso, A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, and G. Teti
Dual Role of TLR2 and Myeloid Differentiation Factor 88 in a Mouse Model of Invasive Group B Streptococcal Disease
J. Immunol., May 15, 2004; 172(10): 6324 - 6329.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. J. Skerrett, H. D. Liggitt, A. M. Hajjar, and C. B. Wilson
Cutting Edge: Myeloid Differentiation Factor 88 Is Essential for Pulmonary Host Defense against Pseudomonas aeruginosa but Not Staphylococcus aureus
J. Immunol., March 15, 2004; 172(6): 3377 - 3381.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
K. Peters, R. E. Unger, J. Brunner, and C.J. Kirkpatrick
Molecular basis of endothelial dysfunction in sepsis
Cardiovasc Res, October 15, 2003; 60(1): 49 - 57.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. Shi, C. Nathan, D. Schnappinger, J. Drenkow, M. Fuortes, E. Block, A. Ding, T. R. Gingeras, G. Schoolnik, S. Akira, et al.
MyD88 Primes Macrophages for Full-Scale Activation by Interferon-{gamma} yet Mediates Few Responses to Mycobacterium tuberculosis
J. Exp. Med., October 6, 2003; 198(7): 987 - 997.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
S. Weijer, M. E. Sewnath, A. F. de Vos, S. Florquin, K. van der Sluis, D. J. Gouma, K. Takeda, S. Akira, and T. van der Poll
Interleukin-18 Facilitates the Early Antimicrobial Host Response to Escherichia coli Peritonitis
Infect. Immun., October 1, 2003; 71(10): 5488 - 5497.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Martin, R. E. Schifferle, N. Cuesta, S. N. Vogel, J. Katz, and S. M. Michalek
Role of the Phosphatidylinositol 3 Kinase-Akt Pathway in the Regulation of IL-10 and IL-12 by Porphyromonas gingivalis Lipopolysaccharide
J. Immunol., July 15, 2003; 171(2): 717 - 725.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Muraille, C. De Trez, M. Brait, P. De Baetselier, O. Leo, and Y. Carlier
Genetically Resistant Mice Lacking MyD88-Adapter Protein Display a High Susceptibility to Leishmania major Infection Associated with a Polarized Th2 Response
J. Immunol., April 15, 2003; 170(8): 4237 - 4241.
[Abstract] [Full Text] [PDF]

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