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2974.Full.Pdf The Production of IL-1 Receptor Antagonist in IFN- β-Stimulated Human Monocytes Depends on the Activation of Phosphatidylinositol 3-Kinase but Not of This information is current as STAT1 of October 1, 2021. Nicolas Molnarfi, Nevila Hyka-Nouspikel, Lyssia Gruaz, Jean-Michel Dayer and Danielle Burger J Immunol 2005; 174:2974-2980; ; doi: 10.4049/jimmunol.174.5.2974 Downloaded from http://www.jimmunol.org/content/174/5/2974 References This article cites 51 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/174/5/2974.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 by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Production of IL-1 Receptor Antagonist in IFN-␤-Stimulated Human Monocytes Depends on the Activation of Phosphatidylinositol 3-Kinase but Not of STAT11 Nicolas Molnarfi, Nevila Hyka-Nouspikel, Lyssia Gruaz, Jean-Michel Dayer, and Danielle Burger2 IFN-␤ induces the production of secreted IL-1R antagonist (sIL-1Ra) without triggering synthesis of the agonist IL-1␤ in human monocytes. This might account for its anti-inflammatory properties. Canonically, IFN-␤ signals through activation of JAK/STAT pathway, although PI3K and MAPK have also been involved. In this study, the role of PI3K, MEK1, and STAT1 in IFN-␤-induced sIL-1Ra production is investigated in freshly isolated human blood monocytes. PI3K, but not MEK1 activation is essential for ␤ sIL-1Ra production in monocytes treated with IFN- , as demonstrated by using the respective inhibitors of PI3K and MEK1, Downloaded from Ly294002 and PD98059. The use of cycloheximide and actinomycin D shows that sIL-1Ra was an immediate early gene induced by IFN-␤ and that PI3K was controlling sIL-1Ra gene transcription. Although both inhibitors of PI3K and MEK1 diminished the Ser727 phosphorylation of STAT1 induced by IFN-␤, only Ly294002 inhibited sIL-1Ra production. Furthermore, the inhibition of STAT1-Ser727 phosphorylation by Ly294002 did not affect STAT1 translocation, suggesting that STAT1 was not involved in sIL-1Ra gene induction. This was confirmed in monocytes that were transfected with small interfering RNA specifically targeting ␤ STAT1. Indeed, monocytes in which effective STAT1 gene knockdown was achieved were fully responsive to IFN- in terms of http://www.jimmunol.org/ sIL-1Ra production. Taken together, the present data demonstrate that the induction of sIL-1Ra transcription and production by IFN-␤ in human monocytes involved PI3K, but not STAT1 activation. The Journal of Immunology, 2005, 174: 2974–2980. nterleukin-1 receptor antagonist (IL-1Ra)3 is a member of the anti-inflammatory cytokines (15–17). However, cellular mecha- IL-1 family. Three protein forms of IL-1Ra resulting from nisms involved in cytokine production and targeted by IFN-␤ in I the same gene have been described, two of them being in- chronic inflammatory diseases remain unclear (11). In human tracellular and the third secreted (sIL-1Ra) (1). The function(s) of monocytes activated by proinflammatory stimuli, IFN-␤ displays the intracellular forms of IL-1Ra is still elusive, but sIL-1Ra binds opposite effects depending on the type of stimulus. Indeed, IFN-␤ competitively to IL-1RI without inducing signal transduction, and inhibits TNF and IL-1␤ production in cell contact-mediated T lym- by guest on October 1, 2021 ␣ ␤ thus inhibits IL-1 and IL-1 actions. Some stimuli induce sIL- phocyte signaling of monocytes (4, 18), in contrast with LPS-ac- 1Ra in the absence of IL-1 production in human monocytes, in- tivated monocytes in which IFN-␤ enhances the production of both ␤ cluding IL-3, IL-4, GM-CSF, leptin, and IFN- (2–5). Other stim- IL-1␤ and TNF (19). However, with the latter stimuli, the produc- uli, such as LPS and direct cellular contact with stimulated T cells, tion of sIL-1Ra is enhanced upon addition of IFN-␤, which as such induce the production of both sIL-1Ra and IL-1␤ (6–8). potently induces the production of sIL-1Ra in monocytes (4). In An imbalance between pro- and anti-inflammatory cytokines contrast, IFN-␤ does not induce IL-1␤ protein or transcript (4, 19). has been involved in the pathology of chronic immunoinflamma- The type I IFN receptor complex (IFNAR) is expressed on most tory diseases, such as multiple sclerosis and rheumatoid arthritis (9, 10). IFN-␤ has proved beneficial to patients with relapsing- cell types and consists of two structurally related polypeptides, one remitting multiple sclerosis (11) and could be a potential therapy of which binds the cytokine (IFNAR-2) and the other transduces for rheumatoid arthritis (12–14). The therapeutic effects of IFN-␤ the signal (IFNAR-1) (for review, see Ref. 20). The canonical ␤ might be due to the restoration of the balance between pro- and pathway of intracellular signaling used by IFN- involves the ac- tivation of the two receptor-associated Janus protein tyrosine ki- nases JAK1 and Tyk2, which in turn activate by tyrosine phos- Division of Immunology and Allergy, Clinical Immunology Unit, Faculty of Medi- phorylation members of the STAT family, STAT1, STAT2, and cine, University Hospital, Geneva, Switzerland STAT3 (20, 21). This leads to the formation of transcriptional Received for publication July 1, 2004. Accepted for publication December 9, 2004. activator complexes, i.e., STAT1-STAT1, STAT1-STAT2, The costs of publication of this article were defrayed in part by the payment of page STAT1-STAT3, and STAT3-STAT3 (22–24). In addition, recep- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tor ligation leads to the recruitment of downstream signaling ele- 1 This work was supported by Grant 3200-068286.02 from the Swiss National Sci- ments, including STAT3 (25) and insulin receptor substrate (IRS) ence Foundation and a grant from the Swiss Society for Multiple Sclerosis. The proteins to IFNAR-1 (26). Both IRS-1 and STAT3 have been authors have no financial conflict of interest. shown to function as adapter proteins, linking IFNAR-1 to the p85 2 Address correspondence and reprint requests to Dr. Danielle Burger, Clinical Im- munology Unit, Division of Immunology and Allergy, Faculty of Medicine, Univer- subunit of PI3K, resulting in enzyme activation (26). However, sity Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail another study demonstrates a direct interaction between PI3K and address: [email protected] IFNAR-1, but not with STAT3 (27). Other transduction pathways 3 Abbreviations used in this paper: IL-1Ra, IL-1R antagonist; GAS, IFN-␥ activation involving MAPK have been shown to modify the JAK-STAT site; IFNAR, type I IFN receptor complex; IRS, insulin receptor substrate; sIL-1Ra, secreted IL-1Ra; siRNA, small interfering RNA. pathway by interacting with IFNAR-1 (28). Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 2975 Several intracellular pathways leading to sIL-1Ra production in Preparation of nuclear extracts and EMSA human monocytes have been described that might depend on the Cell nuclear extracts were prepared, as described previously (36). Protein stimulus or the cell differentiation/maturation stage. MAPK such concentrations were determined by the method of Bradford (37). Nuclear as Raf-1 and ERK1/ERK2 have been involved in sIL-1Ra induc- extracts were analyzed for STAT1-binding activity by EMSA. The binding tion by LPS and leptin (29, 30). In contrast, serine/threonine phos- reaction mixture contained 5 ␮g of protein, 2 ␮g of poly(dI-dC), and 10 ␮g ␮ phatases are involved in the induction of sIL-1Ra in monocytic of BSA in a final volume of 15 l of extraction buffer containing 20% glycerol. Each reaction contained 5 ϫ 104 cpm of unblunted dsSTAT1 cells activated by cellular contact with stimulated T cells (31), and oligonucleotide (5Ј-GTGCATTTCCCGTAAATCTTGTC-3Ј and 5Ј-TG STAT6 mediates the induction of sIL-1Ra by IL-4 (32). Further- TAGACAAGATTTACGGGAAAT-3Ј) that was labeled by fill-in with more, an LPS-inducible PI3K-dependent signaling pathway con- DNA polymerase I large (Klenow) fragment in the presence of 32 tributes to the elevated translation of sIL-1Ra in septic/LPS- [␣- P]dCTP, as described (30). The reaction mixtures were incubated for 1 h at room temperature. Supershift was conducted by adding 100 ␮g/ml adapted leukocytes, a pathway that does not affect the production anti-STAT1 Ab (Upstate Biotechnology) 30 min before the end of the of IL-1␤ (33). The present study addresses the question as to the reaction. Free and bound DNA were separated by electrophoresis on a 4% signaling pathways involved in IFN-␤ induction of sIL-1Ra in hu- nondenaturing polyacrylamide gel in 50 mM Tris, pH 8.0, containing 380 man monocytes. PI3K, but not MEK1 activation is essential for mM glycine and 2 mM EDTA. Gels were dried and subjected to sIL-1Ra production, as demonstrated by using pharmacological autoradiography. inhibitors of PI3K and MEK1. Furthermore, although PI3K is in- STAT1 knockdown volved in Ser727 phosphorylation of STAT1, the latter factor, which is part of the canonical IFN-␤ signaling pathway, is not STAT1 was silenced by using the 4-for-Silencing kit provided by Qiagen.
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