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Session 7. Protein Functions in Cellular Signaling Lectures L7.1 L7.2 Session 7. Protein Functions in Cellular Signaling Lectures L7.2 L7.1 Neutrophil extracellular traps (NETs) in autoinflammatory responses Molecular basis of macrophage Joanna Cichy activation by lipopolysaccharide Jagiellonian University, Faculty of Biochemistry, Biophysics & Katarzyna Kwiatkowska Biotechnology, Department of Immunology, Kraków, Poland e-mail: Joanna Cichy <[email protected]> Nnencki Institute of Experimental Biology, Department of Cell Biology, Warsaw, Poland e-mail: Katarzyna Kwiatkowska <[email protected]> Neutrophils also referred to as polymorphonuclear leuko- cytes (PMNs) form a part of the front line of host defense Lipopolysaccharide (LPS, endotoxin) is a component of against pathogens and are key component of tissue infil- the outer membrane of Gram-negative bacteria. LPS is an trates in autoinflammatory diseases such as systemic lupus archetypical pathogen-associated molecular pattern which erythematosus (SLE) and psoriasis. Activated neutrophils activates of one of Toll-like receptors (TLR), TLR4, of im- can eliminate microbes by the formation of neutrophil ex- mune cells. Upon infection it strongly stimulates production tracellular traps (NETs), extracellular decondensed chro- of pro-inflammatory mediators by macrophages. Excessive matin networks decorated with microbicidal agents. NETs host responses to LPS can lead to a systemic inflammatory were first reported to limit the growth and spread of mi- condition named septic shock. A relatively high incidence croorganisms through mechanically trapping pathogens and mortality of the disease drive studies on molecular and facilitating interaction of anti-microbial agents that are mechanisms of activation of cells by LPS. displayed on NETs with bacteria or fungi. More recently, In a typical scenario, activation of TLR4 is a multistep NETs were associated with tissue damage and autoinflam- process which begins in blood serum with binding of LPS matory diseases. NETs constituents, including self DNA, monomers to LPS-binding protein. The protein transfers histones and myeloperoxidase are potential autoantigens. LPS to CD14, a protein anchored within sphingolipid- Since in addition to their beneficial role in host defense, and cholesterol-rich microdomians (rafts) of the plasma NETs may be an underlying component of cell cytotoxic- membrane. CD14 transfers LPS to TLR4/MD-2 com- ity and autoimmunity, it is likely that specific counter-regu- plex which dimerizes and triggers two signaling pathways latory mechanisms evolved to constrain NETs formation. engaging MyD88 and TRIF adaptor proteins. The TRIF- Here we will discuss our data on regulatory mechanisms dependent signaling pathway requires endocytosis of acti- underlying NETs generation and discuss a contribution of vated TLR4. We study mechanisms which control fast and NETs to a skin disease-psoriasis. reliable organization of TLR4 signaling complexes in the plasma membrane addressing questions such as: Are raft lipids shaping macrophage responses to LPS? What is the role of raft accumulation of CD14 for LPS-triggered sign- aling? Can we identify other raft proteins controlling TLR4 signaling? BIO2014 Congress Session 7. Protein Functions in Cellular Signaling 143 L7.3 Oral presentations NF-kappa B regulation in response O7.1 to LPS and poly(I:C) stimulation Maciej Czerkies1, Zbigniew Korwek1, Wiktor Heme oxygenase-1 deficiency triggers Prus1, Sławomir Błoński1, Bing Tian2, Marek monocyte mobilization and impairs heart Kimmel3, Allan Brasier2, Tomasz Lipniacki1 function after acute myocardial infarction 1Institute of Fundamental Technological Research, Laboratory of Mateusz Tomczyk, Karolina Bukowska-Strakova, Krzysztof 2 Modelling in Biology and Medicine, Warsaw, Poland; University of Szade, Alicja Jozkowicz, Jozef Dulak, Agnieszka Jazwa Texas Medical Branch (UTMB), Department of Internal Medicine, USA; 3Rice University, Department of Statistics, USA Department of Medical Biotechnology, Faculty of Biochemistry, e-mail: Tomasz Lipniacki <[email protected]> Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland e-mail: Agnieszka Jazwa <[email protected]> NF-κB, IRF3 and AP-1 are most potent transcription fac- tors controlling innate immune responses to pathogens. Coronary embolism resulting mostly from atherosclerosis, Combining single cell and population techniques with leads to ischæmic injury of myocardium, subsequent incor- mathematical modeling we analyzed crosstalk of these rect heart contractility and heart failure, the main cause of pathways in mouse embryonic fibroblasts in response to death in industrialized countries. Heme oxygenase-1 (HO- LPS and poly(I:C). 1) is an inducible form of heme-degrading enzyme, which We found that both LPS and poly(I:C) activate mediating possesses cytoprotective, antoxidative and proangiogenic kinases IKKα/β and TBK1; interestingly, only poly(I:C) properties. stimulation leads to activation of IRF3 (activated by TBK1) A role of HO-1 in acute myocardial infarction (AMI) was and triggering of transcription of IFNβ, IRF7, and RIG-1 investigated in HO-1 knock-out and wild type mice ex- and other interferon regulated genes. LPS stimulation leads posed to a permanent ligation of left anterior descending to transient or oscillatory (in some cells) responses of NF- (LAD) coronary artery. Cardiac function was monitored κB, in contrast to switch-like responses (preceded by one weekly for 3 weeks with high frequency ultrasonography or two pulses in a fraction of cells) to poly(I:C) stimula- (Vevo2100 platform) and revealed more potent reduction tion, with fraction of switched-on cells increasing with the of ejection fraction in HO-1 knock-out mice. Coronary stimulation dose. As suggested by the experiment in which artery occlusion in wild type mice lead to strong upregula- cells are costimulated by LPS and IFNβ, the difference in tion of HO-1 expression, with no changes in expression NF-κB responses is caused by IFNβ para- and autocrine of other genes related to iron metabolism (HO-2, ferri- regulation that leads to activation of Eif2ak2 and suppres- tin). Some genotype-dependent differences were observed sion of NF-κB inhibitors synthesis. Correspondingly the in the expression of antioxidant enzymes (superoxide dis- blockade of INFβ receptor causes attenuation of response mutase 1, glutathione peroxidase 1, catalase) and cardiac to poly(I:C) at latter time points. Overall this suggests that myocytes-associated miRNAs (miR-29a, miR-199) at 1, 7 autocrine regulation breaks the negative regulation of NF- and 21 days after AMI. Moreover, we found much higher κB (and IRF3) leading to build up of nuclear NF-κB and numbers of classical (Ly6C++CD43+) and intermediate IRF3, followed by apoptosis in a fraction of cells (not ob- (Ly6C++CD43++) monocytes, both basal and induced by served in the case of LPS stimulation). The IRF3 activation AMI, in peripheral blood of HO-1 deprived mice. Con- is stabilized by positive feedback involving strongly upregu- trary in spleen, we observed higher numbers of classical lated IRF7 and RIG-1 (which is IRF7 responsive). and intermediate monocytes in wild type animals when We confirmed by mathematical modeling the dynamically compared to HO-1 knock-outs. Finally, we noticed that divergent responses to LPS (mimicking bacterial infec- abundance of SKL cells (Sca-1+/c-kit+/Lin-) including hæ- tion) and to poly(I:C) (mimicking viral infection). NF-κB is matopoietic stem cells (HSCs, Sca-1+/c-kit+/Lin-/CD48-/ known for exhibiting oscillatory responses to TNFα, which CD150+/CD34-) populations in bone marrow of HO-1 are replaced by switch-like responses in A20-deficients deprived mice was larger. No differences were found in cells. Here, we found that activation of the IRF3 pathway, case of bone marrow hæmatopoietic progenitor cells (Sca- or INFβ stimulation leads to the similar effect on NF-κB 1+/c-kit+/Lin-/CD48-/CD150-/CD34+) between both signaling, possibly due to inhibition of translation of NF- genotypes. κB inhibitors. The switch-like behavior, frequently associ- Consequences of AMI seem to be more severe in HO-1 ated with cell fate decisions, is associated with bistability knock-out mice. Lack of HO-1 may influence early and late arising here due to the positive feedbacks in IRF3/IRF7 responses to AMI related to antioxidant genes expression regulation. and monocyte/macrophage-dependent cardiac remod- eling. Warsaw, September 9th–12th 2014 144 Session 7. Protein Functions in Cellular Signaling O7.2 O7.3 Silencing of connective tissue growth Physiological and pharmacological factor by small interfering RNA consequences of 2-methoxyestradiol, prevents fibroblasts to myofibroblast a plausible novel hormone transition in bronchial asthma Magdalena Gorska1, Alicja Kuban Jankowska1, Monika Katarzyna Wójcik1,3, Marta Michalik2, Paulina Gorzynik1, Michal Aleksander Zmijewski2, Maciej Wnuk3, Koczurkiewicz3, Zbigniew Madeja2, Marek Sanak1 Iwona Rzeszutek3, Anna Lewinska3, Michal Wozniak1 1Jagiellonian University Medical College, Department of Medicine, 1Department of Medical Chemistry, Medical University of Gdansk, Laboratory of Molecular Biology and Clinical Genetics, Kraków, Gdańsk, Poland; 2Department of Histology, Medical University of Poland; 2Jagiellonian University, Faculty of Biochemistry, Biophysics Gdansk, Gdansk, Poland; 3Department of Genetics, University of and Biotechnology, Department of Cell Biology, Kraków, Poland; Rzeszow, Rzeszow, Poland 3 Jagiellonian University Medical College, Faculty of Pharmacy,
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