PO Box 2345, Beijing 100023, Chin World J Gstroenterol 2005;11(29):4524-4529 www.wjgnet.com World Journl of Gstroenterology ISSN 1007-9327 wjg@wjgnet.com ELSEVIER 2005 The WJG Press nd Elsevier Inc. All rights reserved. BASIC RESEARCH Role of interleukin 18 in cute lung inflmmtion induced by gut ischemi reperfusion Yong-Jie Yng, Yun Shen, Song-Hu Chen, Xi-Rui Ge Yong-Jie Yng, Institute of Biochemistry nd Cell Biology, Shnghi Institutes for Biologicl Sciences, Chinese Acdemy of Sciences; Grdute School of the Chinese Acdemy of Sciences, Shnghi 200031, Chin Yun Shen, Deprtment of Trditionl Chinese Medicine, Shnghi University of Trditionl Chinese Medicine, Shnghi 201023, Chin Song-Hu Chen, Xi-Rui Ge, Institute of Biochemistry nd Cell Biology, Shnghi Institutes for Biologicl Sciences, Chinese Acdemy of Sciences, Shnghi 200031, Chin Supported by the CAS Pilot Project of Knowledge Innovtion Progrm, No. KSCX 2-3-04-03 Correspondence to: Professor Xi-Rui Ge, Cell Resources Center, Shnghi Institutes for Biologicl Sciences, CAS, Shnghi 200031, Chin. gexirui@sibs.c.cn Telephone: +86-21-54920407 Fx: +86-21-54920406 Received: 2004-12-25 Accepted: 2005-01-05 Abstrct AIM: To study the chnges of endogenous interleukin 18 (IL-18) levels nd evlute the role of IL-18 on lung injury following gut ischemi/reperfusion. METHODS: A superior mesenteric rtery occlusion model ws selected for this reserch. The mice were rndomly divided into four groups: Shm opertion (shm), ischemi (0.5 h) followed by different times of reperfusion (I/R), nd I/R pretreted with exogenous IL-18 (I/R+IL-18) or IL-18 neutrlizing ntibody (I/R+IL-18Ab) 15 min before ischemi. Serum IL-18 levels were detected by Western blot nd ELISA, nd the levels of IL-18 in lung tissue were evluted by immunohistochemicl stining. For the study of pulmonry inflmmtion, the lung myeloperoxidse (MPO) contents nd morphologicl chnges were evluted. RESULTS: Gut ischemi/reperfusion induced rpid increse of serum IL-18 levels, peked t 1 h fter reperfusion nd then declined. The levels of IL-18 in lung tissue were grdully enhnced s the progress of reperfusion. Compred with I/R group, exogenous dministrtion of IL-18 (I/R+IL-18) further remrkbly enhnced the pulmonry MPO ctivity nd inflmmtory cell infiltrtion, nd in I/R+IL-18Ab group, the content of MPO were significntly reduced nd lung inflmmtion ws lso decresed. CONCLUSION: Gut ischemi/reperfusion induces the increse of IL-18 expression, which my mke IL-18 ct s n importnt proinflmmtory cytokine nd contribute to gut ischemi/reperfusion-induced lung inflmmtion. 2005 The WJG Press nd Elsevier Inc. All rights reserved. Key words: IL-18; Ischemi; Reperfusion; Inflmmtion Yng YJ, Shen Y, Chen SH, Ge XR. Role of interleukin 18 in cute lung inflmmtion induced by gut ischemi reperfusion. World J Gstroenterol 2005; 11(29): 4524-4529 http://www.wjgnet.com/1007-9327/11/4524.sp INTRODUCTION Multiple orgn dysfunction syndrome (MODS) is the leding cuse of deth in criticlly ill ptients. Although systemic inflmmtion chrcteristic of MODS cn result in dmge to ny orgn, onset of the syndrome is usully herlded by the development of respirtory insufficiency [1,2]. Gut ischemi nd reperfusion (I/R) is prime mechnism tht results in the pthogenesis of MODS prtly dependent on neutrophils [2]. Neutrophils cn be ctivted in response to reperfusion of ischemi tissue or exposure to endotoxin nd pro-inflmmtory cytokines [1]. Activted neutrophils dhere to endothelium through dhesion molecules, resulting in loclized relese of proteses, rective oxygen species (ROS) nd vrious cytokines nd inflmmtory meditors tht contribute to tissue injury nd filure [1,2]. Interleukin 18 (IL-18), known initilly s n IFN-γinducing fctor, is pleiotropic proinflmmtory cytokine nd it hs direct proinflmmtory properties. In this respect, IL-18 induces production of proinflmmtory cytokines such s TNF-α, IL-1β nd chemokines such s IL-8, MIP-1α nd MCP-1 [3,4], nd upregultes expression of dhesion molecules such s ICAM-1, VCAM-1 on endothelil cells [3,5]. Furthermore, IL-18 is found to ctivte neutrophils nd promote neutrophil migrtion, dhesion nd ccumultion in vivo [6]. These dt suggest tht IL-18 my be involved in the inflmmtory injuries ssocited with I/R [1,2,7,8]. Therefore, recent evidence showing tht some locl tissue ischemic injuries re ssocited with incresed IL-18 levels [9,10], nd elevted IL-18 levels hve been detected in response to heptic I/R injury [11]. A direct correltion hs been observed between IL-18 levels nd liver neutrophils sequestrtion nd liver injury, which suggests tht IL-18 is required for fcilitting neutrophil-dependent heptic I/R injury [11]. Similrly, incresed levels of IL-18 hve been detected in isolted tril trbecule during I/R injury [12]. Inhibition of IL-18 or cspse-1 ctivity ttenuted tissue nd circulting levels of IL-18 nd improved myocrdil contrctility, suggesting tht endogenous IL-18 ply significnt role in I/R-induced humn myocrdil injury [12]. Furthermore, Melnikov et l., reported tht cspse-1 nd IL-18 ply n importnt role in the ischemic cute renl filure [13] ; however,
Yng YJ et l. IL-18 in cute lung inflmmtion induced by gut I/R 4525 there is lso evidence suggesting tht ctivted cspse-1 nd its inflmmtory products re not crucil to the induction of inflmmtion fter renl I/R [14]. It is intriguing to consider the role of IL-18 in the I/R-induced locl orgn injury, nd no evidence exists on the role of IL-18 in the MODS following I/R. Therefore, the mjor im of present study ws to determine the chnge of expression nd role of IL-18 in the cute pulmonry injury fter gut ischemi/reperfusion. MATERIALS AND METHODS Regents nd mice C57BL/6J mice (SPF) were obtined from niml center, SIBS, Shnghi. For the experiments, 8-10-wk-old mice weighing 22-26 g were used. rmil-18 ws expressed nd purified in our lb (purity>95% by SDS-PAGE) nd the ctivity ws confirmed by its bility to induce IFN-γ production by mouse spleen cells. For immunohistochemicl nlysis, polyclonl rbbit nti-mouse IL-18 ntibody ws purchsed from Boster (Wuhn, Chin). For immunoprecipittion nd Western blot nlysis, polyclonl rbbit nti-murine IL-18 ntibody ws provided by PeproTech (Rocky Hill, NJ, USA). Ischemi/reperfusion model Mice were nesthetized by intrperitonel injection of urethne (250 mg/ml, 1.25 mg/g wt of mouse, Sigm). The bdomen ws rinsed with 75% ethnol, midline lprotomy ws performed nd the superior mesenteric rtery ws occluded with n rteril clmp. Intestinl ischemi ws confirmed by pulselessness of the mesenteric rtery nd pleness of the jejunum nd ileum. Shm-operted mice underwent the sme procedure, but without vsculr occlusion. After 30 min, the clmp ws removed, sterile sline ws injected into the peritonel cvity for resuscittion, nd the mice were sutured. Experimentl protocols The mice were rndomly divided into four groups (n = 5 in ech): shm, I/R, I/R+IL-18, nd I/R+nti-IL-18. For exogenous IL-18 studies, nimls were pretreted with either IL-18 (5 µg/mouse) or sterile sline vi the lterl til vein 15 min before ischemi. For IL-18 neutrliztion studies, mice received monoclonl nti-il-18 ntibody (25 µg/mouse, MBL, Ngoy, Jpn) or sterile sline 15 min before ischemi. Animls underwent 30 min of superior mesenteric rtery occlusion (or shm opertion) followed by indicted periods of reperfusion were killed, lung tissues, nd blood smples were tken for nlysis. Excised lungs were frozen in liquid nitrogen nd stored t -70 before determintion of myeloperoxidse (MPO) ctivity. For histologicl or immunohistochemicl studies, lungs were immersed in 10% neutrl buffered formlin before sectioning. All blood smples were kept t room temperture for 2 h to clot, nd serum ws removed nd stored t -70 until the time of ssy. Serum IL-18 mesurements Animls underwent crdic puncture to obtin blood t the indicted times in the reperfusion period. Systemic levels of IL-18 were evluted by immunoprecipittion followed by Western blot. Serum ws diluted to 1 ml with PBS, nd serum IL-18 ws immunoprecipitted with rbbit nti-murine IL-18 ntibody. Then, the immunoprecipittes were resolved by SDS-PAGE (12-15% crylmide) under reducing conditions. Gels were trnsferred to NC membrnes nd incubted with primry ntibodies (1:1 000) t 4 overnight. Then mouse nti-rbbit IgG peroxidse ws dded nd developed by ECL. Serum levels of IL-18 were further mesured by ELISA ccording to the mnufcturer s instructions (Boster, Wuhn, Chin). The detection limit for IL-18 ws <5 pg/ml. MPO ssy MPO ctivity is n indictor of neutrophil ccumultion. The content of MPO in the tissues ws mesured s previously described with slight modifiction [7]. The lungs were homogenized for 30 s in 4 ml 50 mmol/l potssium phosphte buffer (ph 6.0) nd then centrifuged for 30 min t 16 000 g t 4. The pellet ws resuspended in 1.5 ml 50 mmol/l potssium phosphte buffer (ph 6.0) contining 5 g/l cetrimonium bromide. The smples were sonicted for 90 s nd then incubted in 60 wter bth for 2 h, nd centrifuged for 30 min t 35 000 g t 4. The superntnt 50 µl ws dded to 950 µl of 50 mmol/l potssium phosphte buffer (ph 6.0) contining 0.167 mg/ml o- dinisidine (Sigm) nd 5 µl/l hydrogen peroxide. Absorbnce of 460 nm ws mesured t 1 nd 3 min. MPO content per grm of wet tissue ws clculted s: MPO content (A/g wet tissue) = (A 460 (3 min)-a 460 (1 min))/tissue weight (g). Histopthology nd immunohistochemistry Lungs were immersed in 10% neutrl buffered formlin before sectioning. Sections (4 µm) were obtined from prffin-embedded tissue smples, stined with hemtoxylineosin (HE), nd exmined for histologicl evlution of tissue dmge under microscope nd photogrphed. For immunohistochemicl nlyses, prffin-embedded lung sections of 4 µm were incubted overnight t 4 with polyclonl rbbit nti-mouse IL-18 ntibody (dilution 1:100). Biotinylted IgG ws dded s second ntibody. Horserdish peroxidse-lbeled streptomycin-vidin complex ws used to detect second ntibody. Slides were stined with diminobenzidine, counterstined with hemtoxylin, nd finlly exmined under light microscope. The brown or drk brown stin ws considered s positive. Sttisticl nlysis All dt re presented s men±sd. Significnt differences between groups were determined using Student s t-test. P<0.05 is considered s sttisticlly significnt. RESULTS TS Ischemi/reperfusion-induced upregultion of IL-18 levels IL-18 hs been shown to be upregulted fter ischemi in the kidney, hert, nd liver. Therefore, we investigted whether the levels of IL-18 chnged in response to gut ischemi/reperfusion. The serum, obtined from shm nd from gut I/R model t different times of reperfusion, ws first evluted by Western blot, nd the chnge of IL-18
4526 ISSN 1007-9327 CN 14-1219/ R World J Gstroenterol August 7, 2005 Volume 11 Number 29 levels is shown in Figure 1A. Two bnds were detected in ll serum smples, which re consistent with the pro nd mture form of IL-18. At time 0, the content of IL-18 from I/R group, for both pro nd mture, ws elevted s compred with tht from shm-operted mice, nd the levels of mture IL-18 (mil-18) ws further considerbly elevted 1 h fter reperfusion, nd then decresed t 3 h (Figure 1A). Mouse serum IL-18 ws further detected by ELISA fter gut ischemi/reperfusion or shm opertion. As shown in Figure 1B, IL-18 levels from norml mouse were <200 pg/ml. Consistent with the previous results, there ws mrked increse in serum IL-18 from I/R group, pek t 1 h (t 660 pg/ml), followed by decline. In the shm group, there ws little mesurble chnge in IL-18 levels during ll reperfusion time. Furthermore, lung tissues obtined from norml mouse nd I/R mice with 1 or 3 h reperfusion ws exmined by immunohistochemistry. Besides the constitutive expression of IL-18 in ir wy epithelium, norml lung tissue lcked immunorective IL-18 (Figure 1C, nd b); during 1-3 h of reperfusion, grdully incresed levels of IL-18 were observed with prominent IL-18 stining (Figure 1C, c nd d). These dt indicted tht IL-18 is induced t the erly phse of ischemi/reperfusion nd my prticipte in the pulmonry inflmmtion. Effects of rmil-18 on lung inflmmtion fter gut I/R Ischemi-induced expression of IL-18 incresed remrkbly t the erly phse of reperfusion, suggesting tht IL-18 my be n erly inflmmtory meditor nd involved in the injurious processes in lung fter gut I/R, which prompted us to suppose whether dministrtion of exogenous IL-18 could exert erly effects on neutrophil ctivtion nd ccelerte lung injury. As shown in Figure 2, in the IL-18- nontreted group, gut ischemi/reperfusion induced grdully incresed MPO ctivity in the lungs t 0.5, 1, or 3 h fter reperfusion (0.65±0.08, 0.86±0.19, or 1.99±0.17 respectively), nd IL-18 injection further drmticlly enhnced the MPO ctivity in the lung tissues t ech indicted times fter reperfusion: the MPO vlue in IL-18-treted mice ws further incresed to 1.54±0.38 ( 237% increse), nd 2.63±0.20 ( 306% increse) t 0.5 or 1 h fter ischemi respectively, s compred with IL-18-nontreted group (P<0.05); nd IL-18 dministrtion induced much more neutrophils infiltrtion in lung within 1 h of reperfusion thn tht of 3 h of reperfusion in IL-18-nontreted group (Figure 2A). Furthermore, fter 3 h of reperfusion, the MPO ctivity ws further incresed to higher level (3.68±0.45, 184% increse) compred with tht from IL-18-nontreted mice (P<0.05). These dt suggested tht IL-18 injection enhnced pulmonry MPO ctivity nd ugmented the neutrophil ccumultion in lung. Lung inflmmtion in this model ws evident from histologicl nlysis (Figure 2B). As previously reported, mssive neutrophil infiltrtion ws observed in the lung tissues from gut I/R model within 3 h of reperfusion (Figure 2B, b). Although the infiltrtion in IL-18-nontreted mice t 1 h fter ischemi ws not obvious (Figure 2B, ), IL-18 injection significntly enhnced the pulmonry infiltrtion fter 1 h of reperfusion (Figure 2B, c). Furthermore, tretment of IL-18 induced more serious inflmmtory cell infiltrtion compred with tht of IL-18-nontreted mice s the reperfusion C b A Pro IL-18 Mt IL-18 Shm (0 h) I/R (0 h) I/R (1 h) I/R (3 h) B 1 000 Norml c d 800 Shm I/R IL-18 pg/ml 600 400 200 0 Norml 0 h 1 h 3 h Figure 1 Gut ischemi/reperfusion results in incresed levels of IL-18 in serum nd lung. (A nd B) The circulting levels of IL-18 fter gut ischemi/reperfusion. Mice were subjected to gut ischemi/reperfusion or shm. Serum IL-18 t the indicted times fter reperfusion ws collected, prt of which ws immunoprecipitted with polyclonl rbbit nti-murine IL-18 ntibody nd nlyzed by immunoblotting (A), nd nother prt ws ssyed with ELISA (B) (n = 5). (C) Gut ischemi/ reperfusion results in elevted levels of IL-18 in lung tissue. Immunohistochemistry of lung sections obtined from norml (, 100, nd b, 200), 1 h (c) or 3 h (d) I/R model. The positive stining for IL-18 shows s drk brown. Mgnifiction (c nd d) 200.
Yng YJ et l. IL-18 in cute lung inflmmtion induced by gut I/R 4527 B b A I/R I/R+IL-18 5 c d MPO (A per g lung) 4 3 2 1 0 0.5 h 1 h 3 h Figure 2 The effect of exogenous IL-18 on the ischemi/reperfusion-induced lung injury. A: IL-18 injection further remrkbly enhnced the neutrophil sequestrtion in lung. After indicted times of reperfusion, the MPO ctivity ws determined in lung tissue (n = 5), P<0.05 vs I/R. B: Comprison of pulmonry histopthology. Lungs from IL-18-nontreted (, for 1 h of reperfusion nd b, for 3 h) or IL-18-treted (c, for 1 h nd d, for 3 h of reperfusion) mice subjected to gut I/R nd stined with HE. Mgnifiction 100. time extended to 3 h (Figure 2B, b nd d), which in ccordnce with the higher MPO ctivity in IL-18-treted group. Both indices of lung inflmmtion, including histologicl chnges nd MPO ctivity, suggest tht IL-18 injection my ccelerte nd ugment the lung inflmmtory injury in response to gut I/R, nd IL-18 my be involved in the lung pthogenesis in this I/R model s n erly inflmmtory meditor. Effects of nti-il-18 on lung inflmmtory induced by gut ischemi/reperfusion To further determine the role of induced IL-18 in the lung pthogenesis, we investigted whether in vivo neutrliztion of IL-18 could modify neutrophil-medited cute inflmmtory response induced by gut I/R. Anti-IL-18Ab (25 µg/mouse) ws dministered 15 min before ischemi insult, nd fter 3 h of reperfusion, the MPO levels were determined nd the lung inflmmtion ws evluted histopthologiclly. As shown in Figure 3, nti-il-18 recipient mice exhibited significntly reduced tissue MPO ctivity (more thn 50% decrese in the lung MPO levels) s compred with the positive control (P<0.05, Figure 3A). Consistent with this, the inflmmtory infiltrtion ws significntly reduced in nti-il-18-treted mice (Figure 3B). These dt suggested the IL-18Ab ttenuted lung inflmmtion induced by gut I/R nd supported the concept tht endogenous IL-18 functioned s n importnt proinflmmtory fctor, which my be involved in the neutrophil sequestrtion nd lung injury in this gut I/R model. DISCUSSION To dte, IL-18 hs been known for its role in infectious A 3.0 2.5 B b MPO (A per g lung) 2.0 1.5 1.0 0.5 0.0 Shm I/R I/R+IL -18 Ab Figure 3 The effect of nti-il-18 ntibody on the ischemi-induced lung injury. A: Anti-IL-18 ntibody injection remrkbly inhibited the lung MPO ctivity. After 3 h of reperfusion, the MPO ctivity ws determined in lung tissues (n = 5), P<0.05 vs others. B: Comprison of pulmonry histopthology. Lungs from ischemic mice (, for 3 h of reperfusion), nd ischemic mice treted with IL-18Ab (b, for 3 h of reperfusion) nd stined with HE. Mgnifiction 100.
4528 ISSN 1007-9327 CN 14-1219/ R World J Gstroenterol August 7, 2005 Volume 11 Number 29 inflmmtory injury. However, few investigtions hve been ccomplished regrding the role of IL-18 during non-infectious cute inflmmtory rections such s those tht occur in ischemi/reperfusion. Previous reports hve shown tht IL-18 hve importnt regultory role during orgn injury induced by locl ischemi/reperfusion [11-13]. In the current study, we used model of cute lung inflmmtion induced by gut ischemi/reperfusion, which results in dmge of cpillry endothelil cells nd neutrophil influx, nd oxidnts, proteses relesed from inflmmtory cells dmge lung cells nd tissue mtrix [1-3]. The role of IL-18 in this model of lung injury hs not been explored. The current study provides evidence tht endogenous IL-18 my ct s proinflmmtory cytokine nd contribute to gut ischemi/ reperfusion-induced lung inflmmtion. Our results, consistent with the previous reports, hve shown tht locl ischemi my induce the elevtion of IL- 18 level [11-13]. It promptly reched pek t 1 h nd then declined to bseline. However, the levels of IL-18 in lung tissue were not the sme. Constitutively, expression of IL-18 in irwy epithelium hs been observed by using immunohistochemistry, nd s the reperfusion time extended to 3 h, the level of IL-18 in ir wy epithelium ws gretly enhnced nd immunorective IL-18 dispersed ll over the lung tissue, which suggests tht pulmonry expression of IL-18 my be enhnced during reperfusion s the inflmmtory gents secreted from intestine reched the lung tissue nd further, the IL-18 receptor medited mechnism my lso ccount for the pulmonry ccumultion of IL-18, which in ccordnce with the rpid decline of serum IL-18 level during reperfusion. IL-18 hs been known to be produced s proform nd stored in cytoplsm. After the clevge of cspse-1, it turns to functionl, mture protein. By Western blot nlysis, the IL-18 mture protein ws quickly incresed fter 1 h of reperfusion (Figure 1A), which suggests tht gut ischemi my result in the ctivtion of cspse-1 nd enhnce the mturtion nd secretion of IL-18. Furthermore, previous reports hve shown tht ischemi lso induces IL-1β expression. Therefore, it is possible tht intestinl cspse-1 my ply key role in expression of both the mture IL-18 nd IL-1β, nd ischemic gut my serve s mjor source for circulting IL-18 in this model. Experimentl studies hve suggested tht IL-18 protects ginst bcteril nd virl gents [3], which is thought to be ttributble in prt to the infiltrtion of inflmmtory cells fter tretment with IL-18. There is lso evidence suggesting tht IL-18 my ctivte neutrophils nd promote neutrophil migrtion nd ccumultion in vivo [6]. In the current studies, we showed tht the in vivo exogenous dministrtion of IL- 18 before gut ischemi gretly enhnced neutrophil recruitment s well s lung inflmmtion (Figure 2). Conversely, IL-18 blockde reduced the evidence of lung inflmmtion by neutrlizing Ab (Figure 3). These results suggest tht IL-18 my, like IL-1β, be n importnt erly pro-inflmmtory cytokine involved in the pthogenesis of cute lung inflmmtion induced by gut ischemi/reperfusion. Furthermore, these dt lso suggest tht the preopertive levels of serum IL-18 my represent vluble prmeter to id the postopertive prognostic determinnt in clinicl ptients with ischemi-induced MODS. But how IL-18 is ctivted, nd how it enhnces the pulmonry inflmmtion during ischemi/reperfusion is still unknown. There is evidence indicting tht NO suppresses IL-18 processing by inhibiting cspse-1 ctivity [15,16]. It is likely tht ischemi-induced decrese of NO levels my result in the ctivtion of cspse-1 nd the further secretion of mture IL-18. Furthermore, it is cler tht IL-18, pleiotropic proinflmmtory cytokine, hs n endogenous role in enhncing production of severl erly response cytokines during lung inflmmtion, such s TNF-α, IFN-γ, nd IL-1β. Previous reports hve shown tht IL-18 my ctivte neutrophil nd promote neutrophil migrtion nd ccumultion in vivo vi TNF-α-dependent pthwy [6,17]. However, the mechnism of pulmonry neutrophils sequestrtion is possibly independent of TNF-α in this lung injury model [18], which suggests tht the function of IL-18 my not be totlly dependent on the role of TNF-α. These works re now in progress in our group. The present dt expnd our knowledge of the immunoregultory properties of IL-18. Our findings re cliniclly pplicble to ischemi/reperfusion injury during surgicl opertion such s smll intestinl trnsplnttion, nd modultion of IL-18 expression my enhnce endogenous protective effects, leding to reduction in orgn injury. REFERENCES 1 Crden DL, Grnger DN. Pthophysiology of ischemireperfusion injury. 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