Modulation of the Phosphoinositide 3-Kinase Pathway Alters Innate Resistance to Polymicrobial Sepsis 1

We examined the effect of modulating phosphoinositide 3-kinase (PI3K) activity in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Inhibition of PI3K activity with wortmannin increased serum cytokine levels and decreased survival time in septic mice. We have reported that an immunomodulator, glucan phosphate, induces protection in murine polymicrobial sepsis. We observed that glucan stimulated tissue PI3K activity, which positively correlated with increased survival in septic mice. We investigated the effect of PI3K inhibition on survival in septic mice treated with glucan. Treatment of mice with the PI3K inhibitors, wortmannin and LY294002, completely eliminated the protective effect of glucan, indicating that protection against septic mortality was mediated through PI3K. Inhibition of PI3K resulted in increased serum levels of IL1-β, IL-2, IL-6, IL-10, IL-12, and TNF-α in septic mice. Apoptosis is thought to play a central role in the response to septic injury. We observed that inhibition of PI3K activity in septic mice resulted in increased splenocyte apoptosis and a change in the anatomic distribution of splenocyte apoptosis. We conclude that PI3K is a compensatory mechanism that suppresses proinflammatory and apoptotic processes in response to sepsis and/or inflammatory injury. Thus, PI3K may play a pivotal role in the maintenance of homeostasis and the integrity of the immune response during sepsis. We also observed that glucan phosphate decreased septic morbidity and mortality through a PI3K-dependent mechanism. This suggests that stimulation of the PI3K pathway may be an effective approach for preventing or treating sepsis and/or septic shock.

[1]  S. Koyasu,et al.  PI3K and negative regulation of TLR signaling. , 2003, Trends in immunology.

[2]  J. Kalbfleisch,et al.  Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality. , 2003, Critical care medicine.

[3]  R. Perng,et al.  Involvement of phosphatidylinositol 3-kinase γ in neutrophil apoptosis , 2003 .

[4]  N. Mackman,et al.  The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells* , 2002, The Journal of Biological Chemistry.

[5]  T. Asano,et al.  PI3K-mediated negative feedback regulation of IL-12 production in DCs , 2002, Nature Immunology.

[6]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[7]  I. Chaudry,et al.  Administration of human inter-alpha-inhibitors maintains hemodynamic stability and improves survival during sepsis. , 2002, Critical care medicine.

[8]  Tsutomu Takeuchi,et al.  Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice , 2002, Nature Immunology.

[9]  L. Cantley,et al.  Phosphoinositide 3-kinase in immunological systems. , 2002, Seminars in immunology.

[10]  I. Chaudry,et al.  Differential Alterations in Cardiovascular Responses During the Progression of Polymicrobial Sepsis in the Mouse , 2002, Shock.

[11]  R. Shenkar,et al.  Involvement of Phosphoinositide 3-Kinases in Neutrophil Activation and the Development of Acute Lung Injury1 , 2001, The Journal of Immunology.

[12]  R. Stein.  Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. , 2001, Endocrine-related cancer.

[13]  L. Moldawer,et al.  SEPSIS SYNDROMES: UNDERSTANDING THE ROLE OF INNATE AND ACQUIRED IMMUNITY , 2001, Shock.

[14]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[15]  L. Moldawer,et al.  Apoptosis in sepsis: a new target for therapeutic exploration , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  David L. Williams,et al.  Early activation of IKKβ during in vivo myocardial ischemia , 2001 .

[17]  N. Olson,et al.  Phosphatidylinositol 3-Kinase Signaling Is Important for Smooth Muscle Cell Replication After Arterial Injury , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[18]  M. Waterfield,et al.  PI3-kinase inhibition: a target for drug development? , 2000, Molecular medicine today.

[19]  J. Kalbfleisch,et al.  inhibition Of Lps-induced Nfκb Activation By A Glucan Ligand Involves Down-regulation Of Ikkβ Kinase Activity And Altered Phosphorylation And Degradation Of Iκbα , 2000 .

[20]  J. Kalbfleisch,et al.  Inhibiting early activation of tissue nuclear factor-κB and nuclear factor interleukin 6 with (1→3)-β-D -glucan increases long-term survival in polymicrobial sepsis , 1999 .

[21]  J. Kalbfleisch,et al.  Early activation of hepatic NFkappaB and NF-IL6 in polymicrobial sepsis correlates with bacteremia, cytokine expression, and mortality. , 1999, Annals of surgery.

[22]  J. Kalbfleisch,et al.  Early activation of pulmonary nuclear factor kappaB and nuclear factor interleukin-6 in polymicrobial sepsis. , 1999, The Journal of trauma.

[23]  M. Quinn,et al.  Modulation of Endotoxin- and Enterotoxin-Induced Cytokine Release by In Vivo Treatment with β-(1,6)-Branched β-(1,3)-Glucan , 1999, Infection and Immunity.

[24]  D. Melican,et al.  Enhanced clearance of a multiple antibiotic resistant Staphylococcus aureus in rats treated with PGG-glucan is associated with increased leukocyte counts and increased neutrophil oxidative burst activity. , 1998, International journal of immunopharmacology.

[25]  J. Dodge,et al.  Structure/activity relationships , 1998 .

[26]  J. Kalbfleisch,et al.  Ligand Binding to the (1 → 3)-β-D-Glucan Receptor Stimulates NFκB Activation, but Not Apoptosis in U937 Cells , 1998 .

[27]  S. Pero,et al.  PGG‐Glucan activates NF‐κB‐like and NF‐IL‐6‐like transcription factor complexes in a murine monocytic cell line , 1997, Journal of leukocyte biology.

[28]  David L. Williams.  Overview of (1→3)-β-D-glucan immunobiology , 1997, Mediators of inflammation.

[29]  R. Bone,et al.  Sir Isaac Newton, sepsis, SIRS, and CARS. , 1996, Critical care medicine.

[30]  Y. Adachi,et al.  Structure-activity relationship of (1-->3)-beta-D-glucans in the induction of cytokine production from macrophages, in vitro. , 1995, Biological & pharmaceutical bulletin.

[31]  L. Moldawer,et al.  BLOCKADE OF TUMOR NECROSIS FACTOR REDUCES LIPOPOLYSACCHARIDE LETHALITY, BUT NOT THE LETHALITY OF CECAL LIGATION AND PUNCTURE , 1995, Shock.

[32]  O. Hazeki,et al.  Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase. , 1995, Trends in biochemical sciences.

[33]  E. Jones,et al.  Comparison of the carbohydrate biological response modifiers Krestin, schizophyllan and glucan phosphate by aqueous size exclusion chromatography with in-line argon-ion multi-angle laser light scattering photometry and differential viscometry detectors. , 1995, Journal of chromatography. B, Biomedical applications.

[34]  E. Jones,et al.  NMR spectral analysis of a water-insoluble (1-->3)-beta-D-glucan isolated from Saccharomyces cerevisiae. , 1994, Carbohydrate research.

[35]  E. Jones,et al.  A method for the solubilization of a (1----3)-beta-D-glucan isolated from Saccharomyces cerevisiae. , 1991, Carbohydrate research.

[36]  M. Tsuchiya,et al.  A novel endotoxin-specific assay by turbidimetry with Limulus amoebocyte lysate containing beta-glucan. , 1991, Journal of biochemical and biophysical methods.

[37]  I. Chaudry,et al.  Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. , 1983, Surgery.

[38]  S. Adi,et al.  Growth Factor-Stimulated Phosphorylation of Akt and p70S6K Is Differentially Inhibited by LY294002 and Wortmannin. , 2001, Endocrinology.

[39]  S. Adi,et al.  Growth factor-stimulated phosphorylation of Akt and p70(S6K) is differentially inhibited by LY294002 and Wortmannin. , 2001, Endocrinology.

[40]  David L. Williams,et al.  IDENTIFICATION OF PHOSPHATE SUBSTITUTION SITES BY NMR SPECTROSCOPY IN A WATER-SOLUBLE PHOSPHORYLATED (13)-BETA -D-GLUCAN , 1998 .

[41]  S. Kohno,et al.  (1↠3)‐β‐D‐Glucan in culture fluid of fungi activates factor g, a limulus coagulation factor , 1995 .

[42]  D. Williams,et al.  Lipid content of microparticulate (1-->3)-beta-D-glucan isolated from Saccharomyces cerevisiae. , 1994, Microbios.