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Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone Gp96

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Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone Gp96 Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone gp96 This information is current as Jin Wang, Anatoly V. Grishin and Henri R. Ford of September 29, 2021. J Immunol 2016; 196:5130-5137; Prepublished online 18 May 2016; doi: 10.4049/jimmunol.1502135 http://www.jimmunol.org/content/196/12/5130 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/05/18/jimmunol.150213 Material 5.DCSupplemental References This article cites 63 articles, 33 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/196/12/5130.full#ref-list-1 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 September 29, 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone gp96 Jin Wang,* Anatoly V. Grishin,*,† and Henri R. Ford*,† Semapimod, a tetravalent guanylhydrazone, suppresses inflammatory cytokine production and has potential in a variety of inflam- matory and autoimmune disorders. The mechanism of action of Semapimod is not well understood. In this study, we demonstrate that in rat IEC-6 intestinal epithelioid cells, Semapimod inhibits activation of p38 MAPK and NF-kB and induction of cyclooxygenase-2 by TLR ligands, but not by IL-1b or stresses. Semapimod inhibits TLR4 signaling (IC50 0.3 mmol) and acts by desensitizing cells to LPS; it fails to block responses to LPS concentrations of ‡5 mg/ml. Inhibition of TLR signaling by Semapimod is almost instanta- neous: the drug is effective when applied simultaneously with LPS. Semapimod blocks cell-surface recruitment of the MyD88 adapter, one of the earliest events in TLR signaling. gp96, the endoplasmic reticulum–localized chaperone of the HSP90 family critically involved in the biogenesis of TLRs, was identified as a target of Semapimod using ATP-desthiobiotin pulldown and mass Downloaded from spectroscopy. Semapimod inhibits ATP-binding and ATPase activities of gp96 in vitro (IC50 0.2–0.4 mmol). On prolonged exposure, Semapimod causes accumulation of TLR4 and TLR9 in perinuclear space, consistent with endoplasmic reticulum retention, an anticipated consequence of impaired gp96 chaperone function. Our data indicate that Semapimod desensitizes TLR signaling via its effect on the TLR chaperone gp96. Fast inhibition by Semapimod is consistent with gp96 participating in high-affinity sensing of TLR ligands in addition to its role as a TLR chaperone. The Journal of Immunology, 2016, 196: 5130–5137. http://www.jimmunol.org/ emapimod (CNI-1493, N, N’-bis [3, 5-diacetylphenyl] The mechanism of action of Semapimod is not well understood. decanediamide tetrakis [amidinohydrazone]) was initially It inhibits activating phosphorylation of MAPKs of p38, JNK, and S designed as a bulky arginine mimetic to limit arginine trans- ERK families in response to inflammatory stimuli (21–23), but it port and NO production during inflammation (1). In addition to the does not directly inhibit these kinases. Although Semapimod di- expected inhibition of inflammatory cytokine-induced arginine rectly inhibits c-Raf (21), a MAPK kinase kinase upstream of transport in macrophages, Semapimod attenuated inflammation and ERK, this does not explain blockade of activation of p38 and JNK, protected against lethal endotoxemia (1). Inhibition of arginine which are independent of c-Raf. Semapimod has been found to uptake and NO production was not the only mechanism responsible directly inhibit deoxyhypusine synthase, an enzyme that catalyzes for the anti-inflammatory effect of Semapimod: the drug inhibited posttranslational modification of the translation initiation factor by guest on September 29, 2021 LPS-induced inflammatory cytokine release by macrophages at 5A, which might explain the antiviral and antimalaria effects (9, concentrations at least 10 times lower than that required for the 24), but not the blockade of inflammatory cytokine production. inhibition of arginine uptake (2). Semapimod inhibits inflammatory Upon intracranial injection, Semapimod potently activates the responses not only in macrophages/monocytes, but also in other cholinergic anti-inflammatory pathway involving the vagus cell types, including endothelial cells (3), dendritic cells (4), and nerve (25, 26); however, this does not explain the drug’s anti- enterocytes (5). Since its discovery, Semapimod has been reported inflammatory effects in vitro. to have a beneficial effect in a broad range of experimental and The intestinal epithelium becomes largely refractory to the TLR clinical inflammatory conditions, such as acute endotoxemia (6, 7), ligands following bacterial colonization, which has been exten- bacterial infection (8), malaria (9), arthritis (10, 11), autoimmune sively demonstrated in the adult, microbiota-associated intestine. encephalomyelitis (12), Alzheimer disease (13), pancreatitis (14), However, the naive epithelium of the neonates possesses TLR re- allograft rejection (15), cancer (16, 17), postoperative ileus (18, 19), sponsiveness similar to that of the professional innate immune cells and Crohn disease (20, 21). (5, 27–31). TLR signaling in the epithelium plays critical role in the pathogenesis of necrotizing enterocolitis, a disease coincident with the onset of bacterial colonization of the gut (29, 32–34). We are *Division of Pediatric Surgery, Children’s Hospital Los Angeles, Los Angeles, CA interested in Semapimod because it improves outcomes of experi- † 90027; and Department of Surgery, University of Southern California, Los Angeles, mental necrotizing enterocolitis (35). Because Semapimod is not CA 90027 absorbed in the intestine (19), it is an attractive drug for organ- ORCID: 0000-0001-9118-9512 (H.R.F.). targeted therapy of intestinal inflammatory disorders. Received for publication October 1, 2015. Accepted for publication April 18, 2016. In this study, we demonstrate that in enterocytes, Semapimod This work was supported by National Institutes of Health Grant R01 AI014032 inhibits TLRs by targeting their common molecular chaperone gp96. (to H.R.F.). Address correspondence and reprint requests to Dr. Anatoly V. Grishin, Division of Pediatric Surgery, Children’s Hospital Los Angeles MS35, 4661 Sunset Boulevard, Materials and Methods Los Angeles, CA 90027. E-mail address: [email protected] Cell culture and reagents The online version of this article contains supplemental material. Abbreviations used in this article: COX-2, cyclooxygenase-2; ER, endoplasmic re- IEC-6, HEK293, and SW480 cell lines were grown as recommended by the ticulum; iNOS, inducible NO synthase; NECA, N-ethyl carboxamidoadenosine; supplier (American Type Culture Collection, Manassas, VA). IEC-6 cells NP-40, Nonidet P-40; Pam3CSK4, tripalmytoyl cysteine-serine-(lysine)4. were used at passages 17–28. For all experiments, cells were plated at 4 to 5 3 104/cm2 and grown overnight to 70–90% confluence. Cell viability Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 was determined by Trypan blue staining. Reagents were purchased from www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502135 The Journal of Immunology 5131 the following suppliers: Semapimod, Medkoo Biosciences (Chapel Hill, activated charcoal was removed by centrifugation. Radioactivity of the clear NC); recombinant canine gp96, catalog number ADI-SPP-766, Enzo Life supernatant was measured by Cerenkov counting. In control reactions, gp96 Sciences (Farmingdale, NY); recombinant human HSP90, catalog number was substituted for equivalent amount of autoclaved porcine collagen. Fol- SPR-101A, StressMarq Biosciences (Victoria, BC, Canada); LPS from lowing background subtraction, data were expressed as percent of charcoal- Escherichia coli 0127:B8, MG132, geldanamycin, radicicol, and N-ethyl absorbed radioactivity in the absence of inhibitor. carboxamidoadenosine (NECA), Sigma-Aldrich (St. Louis, MO); tripalmytoyl Statistical methods cysteine-serine-(lysine)4 (Pam3CSK4), Tocris Bioscience (Bristol, U.K.); ultrapure flagellin from Salmonella typhimurium, Invivogen (San Diego, Quantitative data were expressed as means 6 SD. Data were compared CA); recombinant rat IL-1b, PeproTech (Rocky Hill, NJ); peroxynitrite, using unpaired t test. Cayman Chemical (Ann Arbor, MI); and the ATP-desthiobiotin kit, Thermo Scientific (Rockford, IL). Abs were from the following sources: gp96 (H-212) and TLR4 (H80), Santa Cruz Biotechnology (Santa Cruz, Results CA); TLR9 (SAB2104136) and FLAG M2, Sigma-Aldrich; phospho-p38, Semapimod specifically blocks responses to a subset of TLR p38, phospho-MAPK kinase 3/6, and IkBa, Cell Signaling Technology ligands (Danvers, MA); cyclooxygenase-2 (COX-2), Cayman Chemical; induc- ible NO synthase
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