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Macrophages and STAT Signaling Lactobacilli and Streptococci Activate NF-κB and STAT Signaling Pathways in Human Macrophages This information is current as Minja Miettinen, Anne Lehtonen, Ilkka Julkunen and of October 3, 2021. Sampsa Matikainen J Immunol 2000; 164:3733-3740; ; doi: 10.4049/jimmunol.164.7.3733 http://www.jimmunol.org/content/164/7/3733 Downloaded from References This article cites 62 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/164/7/3733.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 3, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Lactobacilli and Streptococci Activate NF-␬B and STAT Signaling Pathways in Human Macrophages1 Minja Miettinen,2 Anne Lehtonen, Ilkka Julkunen, and Sampsa Matikainen Gram-positive bacteria induce the production of several cytokines in human leukocytes. The molecular mechanisms involved in Gram-positive bacteria-induced cytokine production have been poorly characterized. In this work we demonstrate that both nonpathogenic Lactobacillus rhamnosus GG and pathogenic Streptococcus pyogenes (group A streptococci) induce NF-␬B and STAT DNA-binding activity in human primary macrophages as analyzed by EMSA. NF-␬B activation was rapid and was not inhibited by a protein synthesis inhibitor cycloheximide, suggesting that these bacteria could directly activate NF-␬B. STAT1, STAT3, and IFN regulatory factor-1 DNA binding was induced by both bacteria with delayed kinetics compared with NF-␬B. In addition, streptococci induced the formation of IFN-␣-specific transcription factor complex and IFN-stimulated gene factor-3 (ISGF3). STAT1 and STAT3 activation and ISGF3 complex formation were inhibited by cycloheximide or by neutralization with IFN-␣/␤-specific Abs. Streptococci were more potent than lactobacilli in inducing STAT1, ISGF3, and IFN regulatory factor-1 Downloaded from DNA binding. Accordingly, only streptococci induced IFN-␣ production. The activation of the IFN-␣ signaling pathway by streptococci could play a role in the pathogenesis of these bacteria. These results indicate that extracellular Gram-positive bacteria activate transcription factors involved in cytokine signaling by two mechanisms: directly, leading to NF-␬B activation, and indirectly via cytokines, leading to STAT activation. The Journal of Immunology, 2000, 164: 3733–3740. acrophages have a central role in initiating the innate activation of NF-␬B is followed by the production of TNF-␣ and http://www.jimmunol.org/ immune response, which leads to activation of the further activation of NF-␬B (8, 9). STAT activation occurs via M adaptive response. Macrophages phagocytose infected tyrosine phosphorylation; binding of cytokines to their receptors cells, present Ags to T and B cells, and produce cytokines and results in autophosphorylation of receptor-associated JAK kinases chemokines that modulate immune responses (1). These cytokines that phosphorylate and activate STATs. Activated STATs form include TNF-␣ and IL-6, which are among the first produced dur- homo- or heterodimers that translocate into the nucleus and bind ing the innate immune response toward bacteria. TNF-␣ and IL-6 specific target elements in the promoters of cytokine-inducible have pleiotropic effects such as induction of the acute phase re- genes (10–12). STAT1 and STAT3 can be activated by several sponse and activation of macrophages (2, 3). An innate immune cytokines, including IFN-␣ and IL-6, and bind to the IFN-␥ acti- 3 response to viruses is characterized by rapid production of IFN-␣ vation site (GAS) element. IFN-␣ is the only known activator of by guest on October 3, 2021 in macrophages. In addition to its direct antiviral functions, IFN-␣ STAT2 that, together with STAT1 and p48, form the IFN-stimu- has a range of immunoregulatory functions, including NK cell ac- lated gene factor-3 (ISGF3) (3) complex that binds to the IFN tivation and enhancement of Th1-type immunity (4–7). Although response element (ISRE) (13, 14). the role of IFN-␣ in viral and intracellular bacterial infections is Lactobacilli are nonpathogenic Gram-positive inhabitants of hu- well established, in extracellular bacterial infections it remains man normal microflora (15); some of them have been postulated to poorly characterized. have health beneficial effects, such as stimulation of the immune Cytokines initiate signaling cascades through their receptors, system (16). Strain Lactobacillus rhamnosus GG has been exten- leading to activation of transcription factors and target gene ex- sively studied regarding safety and clinical effects (17). Strepto- pression. NF-␬B and STATs are both latent cytoplasmic transcrip- coccus pyogenes (group A streptococci) is a major Gram-positive tion factors activated by Ag or cytokine stimulation. They regulate human pathogen causing a wide range of infections. Since the transcription of genes encoding proteins involved in immune, 1980s, highly invasive strains associated with shock and organ failure acute phase, and inflammatory responses. In humans, activated have emerged (18). To analyze the mechanisms by which Gram-pos- NF-␬B dimers consist mainly of the Rel family proteins p50 and itive bacteria induce immune responses we have compared nonpatho- p65 subunits. NF-␬B binds to responsive ␬B sites in the promoters genic and pathogenic strains. We have previously shown that L. rh- and enhancers of target genes, including TNF-␣ and IL-6. TNF-␣ amnosus GG and S. pyogenes induce the production of several is known to initiate an autoregulatory feedback loop, where the cytokines in human PBMC (19). In this work we have compared and analyzed the role of live L. rhamnosus GG and S. pyogenes in acti- vation of NF-␬B and STATs in human primary macrophages. Department of Virology, National Public Health Institute, Helsinki, Finland Received for publication July 19, 1999. Accepted for publication January 21, 2000. Materials and Methods The costs of publication of this article were defrayed in part by the payment of page Bacterial strains charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Lactobacillus rhamnosus GG (American Type Culture Collection 53103) was obtained from Valio R&D (Helsinki, Finland), and Streptococcus pyo- 1 This work was supported by the University of Helsinki 350th Anniversary Fund, the genes serotype T1 (IH32030), isolated from a child with bacteremia, was Medical Research Council of the Academy Finland, the Sigrid Juselius Foundation, and the Jenny and Antti Wihuri Foundation. 2 Address correspondence and reprint requests to Dr. Minja Miettinen, Department of 3 Abbreviations used in this paper: GAS, IFN-␥ activation site; ISGF3, IFN-stimulated Virology, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, gene factor-3; ISRE, IFN response element; CHX, cycloheximide; IRF, IFN regulatory Finland. E-mail address: minja.miettinen@ktl.fi factor; TLR, Toll-like receptor; GAS, group A streptococci; SIE, c-sis-inducible element. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 3734 NF-␬B AND STAT ACTIVATION BY GRAM-POSITIVE BACTERIA obtained from the collection of the National Public Health Institute (Hel- sinki, Finland). Bacteria were stored in skimmed milk at Ϫ70°C and pas- saged three times as previously described (20) before their use in stimu- lation experiments. Lactobacilli were grown in MRS medium (Difco, Detroit, MI) and streptococci in TY medium supplemented with 0.2% glu- cose (21). For stimulation experiments bacteria were grown to logarithmic growth phase, and the number of bacterial cells was determined by count- ing in a Petroff Hausser counting chamber. Cell culture Freshly collected leukocyte-rich buffy coats from healthy blood donors were supplied by the Finnish Red Cross Blood Transfusion Service (Hel- sinki, Finland). PBMC were isolated by a density gradient centrifugation over Ficoll-Paque gradient (Pharmacia, Uppsala, Sweden). After washing, the cells were resuspended in RPMI 1640 medium (Sigma, St. Louis, MO) supplemented with 0.6 ␮g/ml penicillin, 60 ␮g/ml streptomycin, 2 mM L-glutamine, and 20 mM HEPES. For monocyte differentiation, PBMC were allowed to adhere to plastic six-well plates (Falcon, Becton Dickin- son, Franklin Lakes, NJ) for1hat37°C in RPMI 1640 medium supple- mented with antibiotics, glutamine, and HEPES without FCS (10 ϫ 106 cells/well). After incubation nonadherent cells were removed, and the wells were washed twice with PBS (pH 7.4). Adherent cells were then grown for 7 days in macrophage/serum-free medium (Life Technologies, Grand Is- Downloaded from land, NY) supplemented with antibiotics and recombinant GM-CSF at 10 ng/ml (Leucomax, Schering-Plough,
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