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Oxygen Radicals and Nitrite Covalent Cross-Linking of Immune

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Oxygen Radicals and Nitrite Covalent Cross-Linking of Immune Covalent Cross-Linking of Immune Complexes by Oxygen Radicals and Nitrite Masaaki Uesugi, Takeshi Hayashi and Hugo E. Jasin This information is current as J Immunol 1998; 161:1422-1427; ; of September 30, 2021. http://www.jimmunol.org/content/161/3/1422 References This article cites 44 articles, 14 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/161/3/1422.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 Subscription Information about subscribing to The Journal of Immunology is online at: by guest on September 30, 2021 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Covalent Cross-Linking of Immune Complexes by Oxygen Radicals and Nitrite1 Masaaki Uesugi,* Takeshi Hayashi,† and Hugo E. Jasin2* We have shown that polymorphonuclear neutrophils mediate the covalent cross-linking of immune complexes (ICs) using H2O2 and myeloperoxidase (MPO). Moreover, activated superficial chondrocytes produce large amounts of nitric oxide (NO), suggesting that high concentrations of these radicals may interact at the cartilage surface in rheumatoid arthritis. We describe the effects of the interaction of NO and its decay product, NO2, with H2O2 and MPO on IC cross-linking. Cross-linking was measured by resistance to the guanidine extraction of plastic-bound ICs. The combination of H2O2, MPO, and NO in the absence of O2 did not alter the magnitude of cross-linking. The addition of O2 resulted in a significant enhancement of cross-linking (p < 0.004), suggesting that nitrite was responsible for the increase observed. Indeed, NaNO2 greatly increased H2O2-dependent cross-linking 6 6 6 Downloaded from (control: 29.2 3.8; 1 mM NaNO2: 58.4 9.9; 10 mM: 60.4 4.2% cross-linking, p < 0.0002). Sodium azide, which is an inhibitor of MPO, completely inhibited cross-linking. These results indicated that the product of interaction of H2O2 and NO2 mediated by MPO may be responsible for the increase in cross-linking. The generation of nitrotyrosine was demonstrated when NO2 was added 2 to the cross-linking system. Cross-linking was also shown with an O2 -generating system and NO. Peroxynitrite alone mediated cross-linking (100 mM ONOO2: 40.3 6 1.9% cross-linking; p < 0.002), and the addition of MPO significantly enhanced this effect (100 mM: 57.7 6 6.0%; p < 0.0002 with respect to no nitrite control). Oxygen radicals and NO are likely to interact at the cartilage surface in inflammatory arthritis, resulting in an increase in oxidative damage within the joint cavity. The Journal of Immu- http://www.jimmunol.org/ nology, 1998, 161: 1422–1427. ighly reactive oxygen-derived species (ROS)3 play im- tightly bound and sequestered on the pannus-free articular surface portant roles in defense mechanisms against infections (13). It was suggested that these complexes gave rise to the phe- H (1) and in tissue injury in inflammatory reactions (2, 3). nomenon of frustrated phagocytosis (14, 15) on the cartilage sur- One of the main reactive products generated by activated phago- face, resulting in the egestion of noxious neutrophil granular com- cytic cells is hypochlorous acid (HOCl), which is formed by the ponent such as ROS and proteases. Indeed, there is abundant enzyme myeloperoxidase (MPO) acting on H2O2 in the presence evidence that a variety of neutrophil products are present at the by guest on September 30, 2021 of chloride ion. This oxidant is mainly responsible for the intra- cartilage surface and at the cartilage-pannus junction (16–19). cellular killing of phagocytosed bacteria (1); it also plays a role in Articular chondrocytes generate large amounts of nitric oxide tissue injury because it mediates the oxidative modification of tis- (NO) when appropriately stimulated with cytokines or bacterial sue macromolecules, the deamination and decarboxylation of pro- products (20, 21). We and others have recently shown that most of teins with the formation of aldehydes, sulfhydryl oxidation, and the oxidant gas is secreted by the chondrocytes located close to the covalent cross-linking (4–10). We have shown previously that articular surface (22, 23). Moreover, recent data indicate that the HOCl is responsible for the covalent cross-linking of proteins, human neutrophil is also able to secrete NO when appropriately 2 namely IgG, resulting in the generation of immune complex (IC)- stimulated (24). Chemical data suggest that NO reacts with O2 like aggregates with phlogogenic capacity (10, 11). Moreover, IgG and other reactive molecules to form stronger oxidant molecules aggregates with evidence of oxidative modification have been such as peroxynitrite (25, 26) and nitryl chloride (27). Similarly, 2 found in the synovial fluids of patients with rheumatoid arthritis the dismutation of O2 by superoxide dismutase and the subse- (12). Previous work in our laboratory also indicated that the ma- quent generation of H2O2 reacting with nitrite in the presence of jority of articular cartilage specimens obtained from patients with MPO may give rise to another strong oxidant, nitrogen dioxide z rheumatoid arthritis contained ICs and complement that were (NO 2) (28). Since the considerations discussed above indicate that high concentrations of ROS, neutrophil granular material such as *Division of Rheumatology and Clinical Immunology, University of Arkansas for MPO, and NO may interact at the articular surface in inflammatory Medical Sciences and John L. McClellan Veterans Administration Center, Little arthritis, the present studies were conducted to study the effects of Rock, AR 72205; and †Department of Orthopedic Surgery, Yokohama City Univer- NO and its decay products on the protein cross-linking activity of sity School of Medicine, Yokohama, Japan neutrophil-derived ROS. Received for publication August 18 1997. Accepted for publication March 30, 1998. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods Reagents 1 This work was supported by U.S. Public Health Service Grant AR-16209. 9 2 Address correspondence and reprint requests to Dr. Hugo E. Jasin, UAMS-Mail Slot Sodium hypochlorite and 5,5 -dithiobis(2-nitrobenzoic acid) were pur- 509, 4301 W. Markham, Little Rock, AR 72205. chased from Sigma (St. Louis, MO). Rabbit anti-BSA Ab was purified as described previously (10, 29). Purified human MPO was a gift from Dr. 3 Abbreviations used in this paper: ROS, reactive oxygen-derived species; IC, im- mune complex; GO, glucose oxidase; MPO: myeloperoxidase; XO: xanthine oxidase; Isaac Ginsburg (Hebrew University, Hadassah School of Dental Medicine, PMN, polymorphonuclear neutrophil; NO, nitric oxide; TNB, 5-thio-2-nitrobenzoic Jerusalem, Israel) (10). NO gas (10% concentration) was purchased from acid; PBS-RS, PBS containing 10% heat-inactivated rabbit serum; SNP, sodium ni- Matheson (Montgomeryville, PA). HOCl was obtained by vacuum distil- troprusside. lation of a 5% solution of sodium hypochlorite (pH 7.5) (30). The resulting Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 1423 product was stored at 280°C. Concentrations were determined by spectropho- e 5 21 21 tometric analysis ( 235 100 M cm ) (31) (Beckman Instruments, Ful- lerton, CA). Mouse monoclonal anti-nitrotyrosine IgG was purchased from Upstate Biotechnology (Waltham, MA). Affinity-purified goat anti-mouse Ig was purchased from Biosource International (Camarillo, CA). Preparation of NO-saturated HBSS HBSS was saturated with NO gas as described by Harry et al. (32) with modifications. A total of 10 ml of HBSS without phenol red was bubbled for 15 min with nitrogen gas and subsequently with 10% NO gas followed by air for 15 min in studies in which the presence of O2 was required. NO-HBSS was prepared freshly before use. NO2 concentrations were de- termined by the Griess reaction (33). Briefly, 100 ml of diluted NO-satu- rated HBSS or standard solution was mixed with 50 ml of 0.1% naphtha- lene diamine dihydrochloride and 50 ml of 1% sulfanilamide, 5% phosphoric acid. Standards were prepared with 10 to 250 mM sodium ni- trite. After a 5-min incubation, the OD at 540 nm was measured with a microplate reader (400ATC, SLT Labs, Triangle Park, NC). Synthesis of 5-thio-2-nitrobenzoic acid (TNB) FIGURE 1. Effect of NO gas in air-saturated HBSS on the H2O2-MPO- The synthesis of TNB was conducted according to Ching et al. (34). A total mediated covalent cross-linking of ICs. Plastic-bound BSA/anti-BSA com- Downloaded from of 20 mM of sodium borohydride was added to a 1 mM solution of 5,59- plexes were incubated for 1 h with 22 mU/ml of MPO and 0.1 U/ml GO 6 dithiobis(2-nitrobenzoic acid) in 50 mM potassium phosphate buffer (pH NO gas. *p , 0.0002; n 5 4. 6.6) plus 5 mM EDTA. The solution was incubated at 37°C for 30 min. The e 5 concentrations were determined by spectrophotometric analysis ( 412 13,600 M21 cm21) (35). Colorimetric assay for H2O2 Synthesis of peroxynitrite Hydrogen peroxide was measured as described by Pick and Keisari (37).
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