Multidrug resistance gene and its relationship to ulcerative colitis and immune status of ulcerative colitis

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1 Multidrug resistnce gene nd its reltionship to ulcertive colitis nd immune sttus of ulcertive colitis Y.J. Zhng 1, J.J. Xu 1, P. Wng 2 nd J.L. Wng 1 1 Deprtment of Gstroenterology, The First Affilited Hospitl of Henn University of Science nd Technology, Luoyng, Henn Province, Chin 2 School of Public Helth, Henn University of Technology, Luoyng, Henn Province, Chin Corresponding uthor: Y.J. Zhng E-mil: zyjhkdyfy1268@163.com Genet. Mol. Res. 13 (4): (2014) Received Jnury 14, 2014 Accepted Mrch 3, 2014 Published December 19, 2014 DOI ABSTRACT. We exmined the reltionship mong the multidrug resistnce (MDR1) gene product P-glycoprotein (P-gp), ulcertive colitis, nd immune sttus under ulcertive colitis. MDR1 P-gp expression nd interleukin-8 levels in ulcertive colitis were determined using immunohistochemistry nd double-ntibody sndwich vidinbiotin complex-enzyme-linked immunosorbent ssy, respectively. Nitric oxide content nd nitric oxide synthse ctivity in the colonic mucos were determined using colorimetric method; CD4 + nd CD25 + T cell subset percentges in the peripherl blood were determined by flow cytometry. The positive expression rte of P-gp in ptients with ulcertive colitis (17.4%) ws significntly lower thn tht in the control group (31.4%). The expression rte decresed to 10.1, 9.2, nd 8.3% fter 12, 18, nd 24 months of tretment, respectively, which were significntly lower thn the expression rte before tretment (17.4%). P-gp expression levels during the remission phse nd ctive phse

2 Y.J. Zhng et l of ulcertive colitis were 15.2 nd 17.1%, respectively, which were significntly lower thn tht in norml controls (31.4%). Compred with P-gp-negtive ptients, nitric oxide content, nitric oxide synthse ctivity, nd interleukin-8 levels were significntly higher in P-gppositive ptients with modertely ctive, severely ctive, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt ulcertive colitis. CD4 + nd CD25 + T cell subsets were significntly lower in the peripherl blood of ptients with severely ctive nd cute fulminnt ulcertive colitis thn in control subjects. Expression of the multidrug resistnce gene nd its product P-gp ws observed in norml colon tissues nd my be closely relted to ulcertive colitis. Key words: Colitis; Drug resistnce; Immune sttus; NOS ctivity; IL-8; CD4 + nd CD25 + T cells INTRODUCTION Recent studies hve indicted tht the multidrug resistnce gene (MDR1) expression product, P-glycoprotein (P-gp), is relted to the pthogenesis of ulcertive colitis (UC) (Mendoz et l., 2007). Potocnik et l. (2004) suggested tht P-gp expression nd ctivity re lower in the peripherl blood, colonic tissue lmin propri, nd colonic intrepithelil lymphocytes in UC ptients compred to control ptients. Frrell nd Kelleher (2003) demonstrted tht inflmmtory bowel diseses, including Crohn s disese nd UC, re resistnt to glucocorticoid nd immunosuppressnt drugs, nd tht ptients requiring surgicl tretment hve higher P-gp levels in peripherl lymphocytes nd the colonic epithelium compred to drug-sensitive nd norml control groups. These results differ from those reported by Potocnik et l. (2004). Studies hve focused on the pthogenesis nd immunologicl mechnisms of UC. Studies exmining the histopthology nd clinicl chrcteristics of UC nd the effectiveness of immunosuppressive therpy indicte tht the immune system plys n importnt role in UC development (Sphn nd Kuchrzlk, 2004). The immune system is n expnsive network tht requires coordintion nd interction between its vrious prts to mintin the body immune response nd immune tolernce. Disruption of ny prt of the immune system cn led to n immune imblnce (Forchielli nd Wlker, 2005). An bnorml response of the body immune system to norml intestinl flor plys mjor role in the pthogenesis of UC, which involves the entire immune response (Thompson-Chgoyán et l., 2005). Multidrug resistnt (MDR1) genes re expressed on both immune nd non-immune cell surfces nd hve multiple functions (Chndrn et l., 2003). Dommels et l. (2007), using FVB wild-type nd FVB multi-drug resistnce gene knockout (MDR1 -/- ) mice, observed P-gp in colitis nd determined the humorl nd cellulr immune function in UC group nd non-uc group of MDR1 -/- mice. A study of the clinicl fetures, pthology, nd immunohistochemistry of UC in 124 MDR1 -/- mice demonstrted tht 24 mice (21%) hd dirrhe, weight loss, nd similr pthology, which ws similr to the symptoms observed in humns with UC, s well s CD4 + T lymphocyte nd B lymphocyte infiltrtion in the colon mucos lmin propri. Serum ntibody nd cytotoxic T lymphocyte function in MDR1 -/- mice without UC were similr to those in wild-type FVB mice. These results indicte tht colitis cn occur in mice lcking MDR1; however, the pthogenesis of

3 Multidrug resistnce gene nd ulcertive colitis colitis is unrelted to the systemic immune response, nd is possibly due to n bnorml locl colonic epithelil cell brrier. Asri et l. (2010) confirmed tht MDR1 is the only P-gp gene expressed in mouse intestinl epithelil cells nd intestinl lymphocytes nd estblished n MDR1 -/- mouse model of inflmmtory bowel disese. In this study, we used immunohistochemicl methods to detect the UC MDR1 gene product P-gp, the double-ntibody sndwich vidin-biotin complex-enzyme-linked immunosorbent ssy (ELISA) method to mesure serum interleukin (IL)-8 levels, colorimetry to mesure nitric oxide (NO) content nd nitric oxide synthse (NOS) ctivity in the colonic mucos, nd flow cytometry to determine peripherl blood CD4 + nd CD25 + T cell subset percentges. The purpose of this study ws to determine the reltionship between the MDR1 product P-gp nd the clinicl chrcteristics of UC in humns. We lso exmined the reltionship with the immune sttus of UC ptients to provide theoreticl nd prcticl bsis for preventing nd mnging UC. MATERIAL AND METHODS Ptients nd controls Ptients were selected from outptients nd inptients treted in the 3 ffilited hospitls of Henn University of Technology, Chin, from Mrch 2007 to December Of the 109 ptients, 68 were mle nd 41 were femle ged yers, with n verge ge of 41.2 yers. In the control group, electronic colonoscopy smples were cquired from 15 ptients without intestinl symptoms who were confirmed to hve norml pthology, no history of irritble bowel syndrome, pst history of UC, nd no drug llergies. Another 20 norml surgicl smples of bowel tissue were obtined from ptients without inflmmtory bowel disese. Of these 35 smples, 19 were from mles nd 16 were from femles ged yers, with n verge ge of 39.4 yers. Study subjects were followed-up for 24 months with strting time indicted by the tretment time or dischrge time. The lst ptient included ws in December 2010 nd ws followed-up until December Ptients were divided into groups, including no-drug group nd groups tht hd been treted with orl minoslicylte drugs, orl or intrvenous corticosteroids, orl or intrvenous corticosteroids nd immunosuppressive gents, topicl ppliction of sulfslzine, 5-minoslicylic cid, glucocorticoids, nd trditionl Chinese medicine. The study protocol ws pproved by the Ethics Committee of Henn University of Technology. Informed consent to prticipte in the study nd undergo surgery ws obtined from ll ptients. Pthologicl dignoses All endoscopic biopsy nd resection specimens were evluted by t lest 2 experienced pthologists. In cses where there ws disgreement, third pthologist reviewed the cse nd gve finl dignosis. Clinicl severity clssifictions In ccordnce with the UC tretment guidelines of the Americn Gstroenterologicl Assocition (Arnold et l., 1998), disese severity ws grded s mild, moderte, or severe.

4 Y.J. Zhng et l Endoscopic grding stndrds According to Bron s improved endoscopic grding stndrds of UC (Sverymuttu et l., 1986), the following grdes were used: grde 0, grde I, grde II, grde III, nd grde IV. Immunohistochemicl stining The streptvidin-peroxidse method ws used nd ntigen retrievl ws required before P-gp mesurement. As negtive control, norml serum ws used rther thn primry ntibody. The remining steps were the sme. The P-gp-positive control ws the serum of colon cncer ptient (Figures 1 nd 2). Figure 1. Negtive expression of P-gp in colonic mucos. SP method 400X. Figure 2. Positive expression of P-gp in the interstitil lymphocyte membrne nd nucleus of colonic epithelil cells. P-gp-positive prticles were minly locted in the lmin propri of the colonic mucos nd intestinl epithelil tissue nd re shown s cler brown color in the cell membrne nd cytoplsm. SP method 400X.

5 Multidrug resistnce gene nd ulcertive colitis Determintion of serum IL-8 levels The double ntibody sndwich vidin-biotin complex ELISA ws used to determine serum IL-8 levels. NO content nd NOS ctivity in colonic mucos Serum levels of NO were mesured using the nitrte reductse ssy. NOS ctivity ws ssessed by mesuring the mount of NO from L-rginine ctlyzed by NOS per unit time. By mesuring totl NOS ctivity nd inducible NOS (inos) ctivity without CCl 2 in the rection solution, the C 2+ -dependent ctlytic rginine nd structurl ctivity ws clculted by subtrcting inos ctivity from totl NOS ctivity. The Biuret method ws used to determine totl protein content in the homogentes. NO concentrtion ws mesured s mmol/g nd NOS ctivity s U/mg. Peripherl blood CD4 + nd CD25 + T cell subsets Sttistics Flow cytometry ws used to determine peripherl blood CD4 + nd CD25 + T cell subsets. The SPSS 10.0 sttisticl pckge ws used for dt entry nd sttisticl nlysis (SPSS, Inc.; Chicgo, IL, USA). Count dt re reported s percentge, nd 2 sets of dt were compred using the Student t-test. The P-gp-positive expression rte in ech group ws compred using the c 2 test. A P vlue of <0.05 ws considered to be significntly different between 2 groups. RESULTS P-gp nd durtion of UC There were 109 cses of UC before nd fter tretment nd 35 norml controls included in this study. Compred to the control group, the P-gp-positive rte ws significntly lower in ptients with UC before nd fter 6, 12, 18, nd 24 months of tretment (P < 0.05). In UC ptients, the P-gp-positive rte ws significntly lower fter 12, 18, nd 24 months of tretment (P < 0.05); however, there ws no significnt chnge fter 6 months of tretment (P > 0.05) (Tble 1). Tble 1. P-gp nd durtion of ulcertive colitis (UC). Durtion of UC N Positive (N) Negtive (N) Positive rte (%) Control Before tretment After tretment 6 months c 12 months bd 18 months bd 24 months bd P < 0.05 vs control; b P < 0.05 vs before tretment; c P > 0.05 vs before tretment; d P < 0.05 vs fter 6 months of tretment.

6 Y.J. Zhng et l P-gp nd clinicl type of UC The clinicl types of UC were divided into erly onset, chronic relpsing, chronic persistent, nd cute fulminnt. Positive P-gp expression in ll clinicl types ws significntly lower thn in control subjects (P < 0.05); there ws no significnt difference between the erly onset type nd chronic relpsing or chronic persistent types (P > 0.05). The P-gp-positive expression rte in the cute fulminnt type ws significntly lower thn tht in the erly onset type (P < 0.05) (Tble 2). Tble 2. P-gp nd clinicl type of ulcertive colitis. Clinicl type N Positive (N) Negtive (N) Positive rte (%) Control Erly onset Chronic relpsing b Chronic persistent b Acute fulminnt c P < 0.05 vs control; b P > 0.05 vs erly onset; c P < 0.05 vs erly onset. Disese ctivity in 76 cses ws divided into mild, moderte, nd severe. The P-gp expression rte in mild, moderte, nd severe disese ws significntly different from tht in controls (P < 0.05). No significnt difference in the P-gp expression rte ws observed in moderte nd severe disese compred to tht in mild disese (P > 0.05) (Tble 3). Tble 3. P-gp nd the severity of ctive ulcertive colitis. Severity N Positive (N) Negtive (N) Positive rte (%) Control Active mild Active moderte b Active severe b P < 0.05 vs control; b P > 0.05 vs ctive mild. P-gp nd the severity of UC P-gp nd clinicl stges According to the clinicl stge, UC cses were clssified s being in remission or being ctive. The P-gp-positive expression rte in the remission nd ctive stge ws significntly lower thn tht in controls (P < 0.05); however, no difference ws observed between the ctive nd remission stges (P < 0.05) (Tble 4). Tble 4. Reltionship between P-gp nd clinicl stge. Stge N Positive (N) Negtive (N) Positive rte (%) Control Remission Active b P < 0.05 vs control; b P > 0.05 vs remission.

7 Multidrug resistnce gene nd ulcertive colitis Reltionship between NO content, NOS ctivity, nd P-gp in colonic mucos Compred with norml controls, NO content nd NOS ctivity in the colonic mucos were significntly incresed in ctive mild, moderte, nd severe disese, s well s in erly onset, chronic relpsing, chronic persistent, nd cute fulminnt disese (P < 0.05). NO content nd NOS ctivity in colonic mucos incresed significntly in ctive vs remission cses, moderte nd severe vs mild cses, nd in cute fulminnt vs erly onset cses (P < 0.05). NO content nd NOS ctivity incresed significntly in ctive moderte, ctive severe, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt disese in P-gp-positive ptients compred with P-gp-negtive ptients (P < 0.05) (Tbles 5 nd 6, Figures 3 nd 4). Tble 5. Comprison of NO content in colonic mucos (mens ± SD) (mmol/g). Group N P-gp-positive P-gp-negtive Control ± ± 2.52 Clinicl stge Remission ± ± 3.96 Active ± 4.69 b ± 4.92 bf Severity Mild ± ± 5.14 Moderte ± 5.19 c ± 4.74 cf Severe ± 9.82 c ± 9.15 cf Clinicl type Erly onset ± ± 2.74 f Chronic relpsing ± 8.35 e ± 6.52 ef Chronic persistent ± 4.61 e ± 5.37 ef Acute fulminnt ± 8.72 d ± 9.44 df P < 0.05 vs control; b P < 0.05 vs remission; c P < 0.05 vs mild; d P < 0.05 vs erly onset; e P > 0.05 vs erly onset; f P < 0.05 vs P-gp-positive. Tble 6. Comprison of NOS ctivity in colonic mucos (mens ± SD) (U/mg). Group N P-gp-positive P-gp-negtive Control ± ± 2.66 Clinicl stge Remission ± ± 3.51 Active ± 4.51 b ± 3.51 bf Severity Mild ± ± 4.57 Moderte ± 4.66 c ± 4.16 cf Severe ± 5.37 c ± 5.63 cf Clinicl type Erly onset ± ± 5.82 f Chronic relpsing ± 6.55 e ± 5.11 ef Chronic persistent ± 5.18 e ± 6.17 ef Acute fulminnt ± 7.62 d ± 3.62 df P < 0.05 vs control; b P < 0.05 vs remission; c P < 0.05 vs mild; d P < 0.05 vs erly onset; e P > 0.05 vs erly onset; f P < 0.05 vs P-gp-positive. Reltionship between serum IL-8 levels nd P-gp Serum IL-8 levels were incresed significntly in ctive mild, moderte, nd severe disese, s well s in erly onset, chronic persistent, nd cute fulminnt disese compred with the controls (P < 0.05). Serum IL-8 incresed significntly in ctive vs remission, mod-

8 Y.J. Zhng et l erte nd severe vs mild, s well s in cute fulminnt vs erly onset disese (P < 0.05). In ddition, IL-8 incresed significntly in ctive, severe, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt disese in P-gp-positive ptients compred with P-gp-negtive ptients (P < 0.05) (Tble 7, Figure 5). Figure 3. Comprison of NO content in colonic mucos. Figure 4. Comprison of NOS ctivity in colonic mucos.

9 Multidrug resistnce gene nd ulcertive colitis Tble 7. Comprison of IL-8 levels in the different groups (mens ± SD) (pg/ml). Group N P-gp-positive P-gp-negtive P Control ± ± Clinicl stge Remission ± ± Active ± b ± bf <0.05 Severity Mild ± ± Moderte ± c ± 5.19 c Severe ± c ± 9.82 cf <0.05 Clinicl type Erly onset ± ± f <0.05 Chronic relpsing ± e ± ef <0.05 Chronic persistent ± e ± ef <0.05 Acute fulminnt ± d ± df <0.05 P < 0.05 vs control; b P < 0.05 vs remission; c P < 0.05 vs mild; d P < 0.05 vs erly onset; e P > 0.05 vs erly onset; f P < 0.05 vs P-gp-positive. Figure 5. Comprison of serum IL-8 levels in different groups (pg/ml). Reltionship between peripherl blood CD4 + nd CD25 + T cell subsets nd P-gp Peripherl blood CD4 + nd CD25 + T cell subset percentges decresed significntly in ctive, mild, moderte, nd severe disese, s well s in erly onset, chronic persistent, nd cute fulminnt disese compred with in controls (P < 0.05). Peripherl blood CD4 + nd CD25 + T cell subset percentges decresed significntly in ctive vs remission, moderte nd severe vs mild, s well s in cute fulminnt vs erly onset disese (P < 0.05). Peripherl blood CD4 + nd CD25 + T cell subset percentges decresed significntly in ctive, severe, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt disese in P-gp-positive ptients compred with P-gp-negtive ptients (P < 0.05) (Tble 8, Figure 6).

10 Y.J. Zhng et l Tble 8. Comprison of peripherl blood CD4 + nd CD25 + T cell subset percentge (mens ± SD). Group N P-gp-positive P-gp-negtive P Control ± ± 0.19 Clinicl stge Remission ± ± 0.14 Active ± 0.27 b 0.44 ± 0.43 bf <0.05 Severity Mild ± ± 0.28 Moderte ± 0.31 c 0.20 ± 0.35 c Severe ± 0.26 c 0.19 ± 0.82 cf <0.05 Clinicl type Erly onset ± ± 0.34 f <0.05 Chronic relpsing ± 0.34 e 0.32 ± 0.31 ef <0.05 Chronic persistent ± 0.23 e 0.34 ± 0.57 ef <0.05 Acute fulminnt ± 0.25 d 0.17 ± 0.32 df <0.05 P < 0.05 vs control; b P < 0.05 vs remission; c P < 0.05 vs mild; d P < 0.05 vs erly onset; e P > 0.05 vs erly onset; f P < 0.05 vs P-gp-positive. Figure 6. Comprison of peripherl blood CD4 + nd CD25 + cell subset (%). DISCUSSION In this study, we found tht the expression of P-gp in ptients with UC before nd fter 6, 12, 18, nd 24 months of tretment ws lower thn tht in the control group. There ws no difference in P-gp expression before tretment nd 6 months fter tretment; however, the rtes of P-gp-positive ptients fter 12, 18, nd 24 months of tretment were significntly different from those before tretment. These findings indicte tht regrdless of the type of UC, expression of the MDR1 product, P-gp, is lower in UC ptients thn in norml helthy individuls. These findings lso demonstrte tht P-gp expression is not relted to the durtion of disese; s disese durtion incresed, P-gp becme lower. It is uncler why P-gp expression ws significntly lower in ptients with cute fulminnt UC.

11 Multidrug resistnce gene nd ulcertive colitis Multidrug resistnce is the most importnt cellulr defense mechnism of tumor cells to void ttck by chemotherpeutic gents (Gutmnn et l., 2008), nd multidrug resistnce ws initilly identified in the study of drug resistnce in tumor cells. However, P-gp is present not only in tumor cells, but lso in norml cells (Fedier et l., 2007), nd the results of this study showed tht the multidrug resistnce gene ws present in norml controls, indicting intrinsic multidrug resistnce. Expression of the drug resistnce gene ws significntly lower in ptients with UC before tretment nd during erly tretment thn in controls. As disese durtion incresed, the drug resistnce gene expression rte decresed; lowered P-gp expression cn weken the intestinl protective effect nd increse disese ctivity. P-gp expression rtes in remission or ctive UC, regrdless of disese severity, were significntly reduced compred with norml controls, nd no differences were observed between remission nd ctive disese or between ptients with different disese severity. Therefore, irrespective of whether UC ws in remission or ctive, P-gp expression ws lower thn tht in norml helthy individuls. Similr results were demonstrted for the positive expression of P-gp in UC; however, this ws not relted to disese severity or ctive or remission sttus. The positive expression rtes in ll lesions were significntly different compred with norml controls. However, no differences were observed mong lesions in different loctions, i.e., stright sigmoid colon lesions, left colon lesions, extensive colon lesions, nd rectl lesions. No significnt difference in the P-gp expression rte ws observed in UC ptients without vs with extr-intestinl lesions. These results suggest tht expression of the MDR1 product, P-gp, in UC is relted to disese occurrence. Ptients with UC my hve inherent chnges in drug resistnce gene expression; the disese my occur with decresed P-gp expression nd the extent of disese nd extr-intestinl mnifesttions re irrelevnt. Studies exmining utoimmune diseses nd orgn trnsplnttion found tht P-gp is the most importnt fctor ffecting the efficcy of corticosteroids, cyclosporin A, FK506, cyclophosphmide, zthioprine, nd other immunosuppressive gents (Verbon et l., 2002). The high expression of P-gp in the peripherl blood lymphocytes of ptients with systemic lupus erythemtosus resulted indecresed lymphocyte glucocorticoid levels, steroid-resistnce, nd reduced efficcy (Hibi et l., 2003). A study by Wsilewsk et l. (2007) lso showed tht steroid-resistnce or -dependence in children with nephrotic syndrome ws relted to P-gp expression in peripherl lymphocytes. The reltionship between P-gp expression nd the immune sttus of ptients with UC in this study showed the following results: compred with norml controls, NO content nd NOS ctivity in the colonic mucos were significntly incresed in ctive, ctive mild, moderte, nd severe disese, s well s erly onset, chronic relpsing, chronic persistent, nd cute fulminnt disese. NO content nd NOS ctivity incresed significntly in ctive vs remission, moderte or severe vs mild, nd cute fulminnt vs erly onset disese, respectively. In ddition, NO content nd NOS ctivity were significntly incresed in P-gp-positive ptients compred to P-pg-negtive ptients with ctive, moderte, severe, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt UC. These results indicte tht NO content nd NOS ctivity in the colonic mucos ws significntly incresed in UC independently of disese severity. In ptients with high P-gp expression, increses in NO content nd NOS ctivity were even more significnt.

12 Y.J. Zhng et l Increses in NO content nd NOS ctivity were more significnt in UC ptients with high P-pg expression; these vlues incresed with disese durtion nd severity. This my hve resulted from recognition of the drug s foreign body; therefore, P-gp plys very importnt role in drug bsorption nd distribution in the body. A previous study found tht vrious drugs re substrtes of P-gp nd tht P-gp substrtes in the cytoplsm ccumultes to high concentrtions in the phospholipid bilyer nd re then trnsferred to the substrte-binding site. ATP hydrolysis occurs t ATP-binding sites s n energy source, nd the drug is then dischrged into the extrcellulr region. As result, P-gp reduces the orl biovilbility of substrtes nd MDR tumor cell toxicity, limiting the effects of the drugs (Hrtz et l., 2004). Alterntively, this my lso result from both internl drug resistnce chnges in UC nd the development of inflmmtion (Sls et l., 2002). Recent studies showed tht endogenous NO is involved in the gstrointestinl mucosl brrier nd the inflmmtory process. NO is closely relted with colonic disese nd n NOS-inducer exists in UC. Incresed inos nd NO re chrcteristic of UC, nd when subjected to certin cytokines, pthogenic microorgnisms, nd other stimuli for few hours, lrge mount of inos is generted, which leds to incresed NO synthesis (Seril et l., 2007). As result of drug resistnce, UC becomes refrctory to tretment, leding to the spred of inflmmtion nd disese progression. This, in turn, significntly increses NO content nd NOS ctivity. NO produced by ctlytic rginine nd structurl NOS is thought to protect the intestinl mucos, while NO produced by inos is toxic nd increses inflmmtion. Decresed production of NO results in smooth muscle contrction, which is likely the most importnt fctor cusing bowel movement disorders nd mucosl dmge, indicting tht, under certin circumstnces, inos hs protective effect. Therefore, smll mount of NO is physiologiclly protective, while lrge mount of NO increses inflmmtion nd cuses dmge (Guihot et l., 2000). IL-8 is primrily produced by mononucler mcrophges nd endothelil cells when stimulted by other cytokines. Its min biologicl role is the chemotxis of eosinophils, neutrophils, bsophils, nd T cells. It lso promotes neutrophil lysosoml enzyme ctivity nd phgocytosis, s well s induces neutrophil degrnultion. IL-8 is powerful leukocyte chemotctic fctor nd ctivtor nd n effective inflmmtory chemokine. Subcutneous injection of IL-8 into nimls results in lrge locl ccumultion of neutrophils nd histopthologicl chnges of cute inflmmtion (Sngfelt et l., 2002). The inflmmtory response induced by IL-1, tumor necrosis fctor (TNF)-α, nd IL-6 is considered to be minly medited by chemokines, nd IL-8 is one of the most importnt chemokines. This study demonstrted tht IL-8 ws significntly incresed in ctive, mild, moderte, severe, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt UC compred to controls (P < 0.05). Serum IL-8 levels incresed in ctive vs remission, moderte nd severe vs mild, nd cute fulminnt vs erly onset disese (P < 0.05). In ddition, serum IL-8 levels significntly incresed in ctive, severe, nd cute fulminnt UC in P-gp-positive ptients compred to in P-gp-negtive ptients (P < 0.05). Higher P-gp expression in UC ws correlted with higher IL-8 levels, which ws more obvious s the durtion nd severity of UC incresed. This my be either the result of drug tretment or the result of n interction between the internl resistnce of UC nd the development of inflmmtion. Fn et l. (2009) investigted the reltionship between inflmmtory bowel disese ctivity nd serum IL-8 nd TNF-α levels nd showed tht serum IL-8 nd TNF-α incresed in UC ptients compred to those in remission nd norml controls. Incresed IL-8 nd TNF-α contribute to mucosl inflmmtory dmge. Drug resistnce in

13 Multidrug resistnce gene nd ulcertive colitis UC increses inflmmtion nd significntly increses NO, NOS, nd IL-8. P-gp is n importnt physiologicl trnsporter protein, nd is minly involved in norml tissue detoxifiction, removl of toxic substnces in vivo, hormone secretion, trnsport of certin substnces, nd the protection of norml tissue cells ginst dmge cused by exogenous toxins. Drugs re considered by the body to be foreign substnces; thus, P-gp lso plys very importnt role in drug bsorption nd distribution. P-gp cn dischrge drugs from the cell; therefore, P-gp cn reduce the orl biovilbility of substrte drugs (Ufer et l., 2009). Vrious studies hve suggested tht bnorml immune nd inflmmtory responses in the intestinl mucos ply n importnt role in the pthogenesis of UC, nd T cells re the primry immune cells involved in these responses. UC is n utoimmune disese involving immune response, genetic, environmentl, nd other fctors. T cells re key immune cells in norml intestinl mucosl immune responses (Sheikh et l., 2008). T cells exert their effect minly through T cell ntigen receptor-medited ntigen recognition, ctivtion, cytotoxicity, cytokine production, nd secretion to protect the intestinl mucos, remove dmged epithelil cells, resist the invsion by foreign ntigens, nd blnce the intestinl environment so tht the intestine cn function normlly. If there is n imblnce in the intestinl mucosl immunity nd inflmmtion, this will inevitbly led to intestinl mucosl dmge nd colitis. The results of this study showed tht the peripherl CD4 + nd CD25 + subset percentges significntly decresed in ctive, mild, moderte, nd severe disese, erly onset, chronic relpsing, chronic persistent, nd cute fulminnt UC compred to norml controls. The peripherl CD4 + nd CD25 + subset percentge decresed significntly in ctive vs remission, moderte nd severe vs mild, nd cute fulminnt vs erly onset disese (P < 0.05). The peripherl CD4 + nd CD25 + subset percentge lso decresed significntly in ctive, severe, nd cute fulminnt disese in P-gp-positive ptients compred to P-gp-negtive ptients. In norml mucosl tissues, effector T cells nd regultory T cells re in stte of dynmic equilibrium to mintin intestinl mucos homeostsis nd immune system stbility. If there re too mny effector T cells or enhnced immunogenicity, the effect of effector T cells will surpss tht of regultory T cells; if there is decrese in the number of regultory T cells or functionl bnormlities, both cn upset the blnce between the two, leding to mucosl injury nd inflmmtory bowel disese (Sumid et l., 2008). Among the peripherl T-cell subsets, CD4 + T cells hve been identified s the min effector cells leding to intestinl inflmmtion nd re the min cell type found in mucosl tissue infiltrtion in ll colitis models. In some studies, inflmmtion ws improved fter removl of CD4 + T cells from the body, nd specific expression of the forkhed/winged helix trnscription fctor in CD4 + nd CD25 + regultory T cells cn effectively prevent UC (Sitohy et l., 2008). Regultory T cells include Trl, which secretes high levels of IL-10, nd Th3, which minly secretes TGF-b. In ddition, forkhed/winged helix trnscription fctoris specificlly expressed in CD4 + nd CD25 + regultory T-cells. CD4 + nd CD25 + regultory T-cells ply n importnt role in the development of Th3 for Trl. Regultory T cells differ from helper T cells; Thl nd Th2 re T cells with immune regultion function nd ply n importnt regultory role in vriety of utoimmune diseses. Regultory T cells were first reported by Skguchi et l. (2004). Direct cell contct nd the relese of TGF-b, IL-10, nd other cytokines cn suppress utorective T cells nd reduce Th1 functions, which is importnt in immune tolernce nd mintining the blnce of immune function. This study lso confirmed tht immune injury plys very importnt role in the ptho-

14 Y.J. Zhng et l genesis of UC. This results becuse the entire immune system, including NO content nd NOS ctivity, significntly increses inflmmtion. The inflmmtory effect of IL-8 nd CD4 + nd CD25 + regultory T cells on immune nd inflmmtory responses in the intestinl mucos ws lso confirmed. Multidrug resistnce gene overexpression in UC my result from either intrinsic lesion development or drug-induced secondry resistnce. UC becomes refrctory becuse of drug resistnce with progression of inflmmtory lesions. As result, NO content nd NOS ctivity increse, nd the inflmmtory effects of IL-8, s well s the effect of CD4 + nd CD25 + regultory T cells in the immune nd inflmmtory responses in the intestinl mucos re significntly enhnced. This multi-drug resistnce gene overexpression is relted to the durtion nd inflmmtory ctivity of UC. CONCLUSION Expression of the multidrug resistnce gene product, P-gp, is closely relted to the durtion of UC; the longer the durtion of UC, the lower the P-gp expression. Expression of the multidrug resistnce gene nd its product, P-gp, is found in norml colon tissue nd is closely relted to UC. Decresed expression of the multidrug resistnce gene nd P-gp my cuse UC. In ptients expressing the multidrug resistnce gene nd P-gp, immune injury plys more importnt role in the pthogenesis of UC. ACKNOWLEDGMENTS Reserch supported by the Scientific Reserch Foundtion of the Doctor (# ). REFERENCES Arnold C, Mordpour D nd Blum HE (1998). Tuberculosis colitis mimicking Crohn s disese. Am. J. Gstroenterol. 93: Asri A, Knemitsu T nd Kurihr H (2010). Orl dministrtion of high moleculr weight hyluronn (900 kd) controls immune system vi Toll-like receptor 4 in the intestinl epithelium. J. Biol. Chem. 285: Chndrn P, Stthpom S, Robins A nd Eremin O (2003). Inflmmtory bowel disese: dysfunction of GALT nd gut bcteril flor (II). Surgeon 1: Dommels YE, Butts CA, Zhu S, Dvy M, et l. (2007). Chrcteriztion of intestinl inflmmtion nd identifiction of relted gene expression chnges in mdr1(-/-) mice. Genes Nutr. 2: Fn H, Shen L, Tng Q, Xiong P, et l. (2009). Effect of Wumeiwn on cytokines TNF-lph, IL-6, IL-8, IL-10 nd expression of NF-kppBp65 in rts with ulcertive colitis. J. Huzhong Univ. Sci. Technol. Med. Sci. 29: Frrell RJ nd Kelleher D (2003). Glucocorticoid resistnce in inflmmtory bowel disese. J. Endocrinol. 178: Fedier A, Dedes KJ, Imesch P, Von Bueren AO, et l. (2007). The histone decetylse inhibitors suberoylnilide hydroxmic (Vorinostt) nd vlproic cid induce irreversible nd MDR1-independent resistnce in humn colon cncer cells. Int. J. Oncol. 31: Forchielli ML nd Wlker WA (2005). The role of gut-ssocited lymphoid tissues nd mucosl defence. Br. J. Nutr. 93: S41-S48. Guihot G, Guimbud R, Bertrnd V, Nrcy-Lmbre B, et l. (2000). Inducible nitric oxide synthse ctivity in colon biopsies from inflmmtory res: correltion with inflmmtion intensity in ptients with ulcertive colitis but not with Crohn s disese. Amino Acids 18: Gutmnn H, Hruz P, Zimmermnn C, Strumnn A, et l. (2008). Brest cncer resistnce protein nd P-glycoprotein expression in ptients with newly dignosed nd therpy-refrctory ulcertive colitis compred with helthy controls. Digestion 78: Hrtz AM, Buer B, Fricker G nd Miller DS (2004). Rpid regultion of P-glycoprotein t the blood-brin brrier by endothelin-1. Mol. Phrmcol. 6:

15 Multidrug resistnce gene nd ulcertive colitis Hibi T, Ngnum M, Kithor T, Kinjyo F, et l. (2003). Low-dose zthioprine is effective nd sfe for mintennce of remission in ptients with ulcertive colitis. J. Gstroenterol. 38: Mendoz JL, Urcely E, Ln R, Mrtín MC, et l. (2007). MDR1 polymorphisms nd response to zthioprine therpy in ptients with Crohn s disese. Inflmm. Bowel Dis. 13: Potocnik U, Ferkolj I, Glvc D nd Den M (2004). Polymorphisms in multidrug resistnce 1 (MDR1) gene re ssocited with refrctory Crohn disese nd ulcertive colitis. Genes Immun. 5: Skguchi E, Skid I nd Okit K (2004). Th1/Th2 blnce in HCV-relted liver cirrhosis nd the effect of TGF-bet on Th1 response: possible implictions for the development of heptom. Nihon. Rinsho. 62 (Suppl 7): Sls A, Gironell M, Sls A, Sorino A, et l. (2002). Nitric oxide supplementtion meliortes dextrn sulfte sodiuminduced colitis in mice. Lb. Invest. 82: Sngfelt P, Crlson M, Thörn M, Xu S, et l. (2002). Locl relese of humn neutrophil lipoclin (HNL), IL-8, nd TNFlph is decresed s response to topicl prednisolone tretment in distl ulcertive colitis nd proctitis. Dig. Dis. Sci. 47: Sverymuttu SH, Hodgson HJ, Chdwick VS nd Pepys MB (1986). Differing cute phse responses in Crohn s disese nd ulcertive colitis. Gut 27: Seril DN, Lio J nd Yng GY (2007). Colorectl crcinom development in inducible nitric oxide synthse-deficient mice with dextrn sulfte sodium-induced ulcertive colitis. Mol. Crcinog. 46: Sheikh S, Uno J, Mtsuok K nd Plevy S (2008). Abnorml mucosl immune response to ltered bcteril flor following restortive proctocolectomy in ptients with ulcertive colitis: serologic mesures, immunogenetics, nd clinicl correltions. Clin. Immunol. 127: Sitohy B, Hmmrström S, Dnielsson A nd Hmmrström ML (2008). Bsl lymphoid ggregtes in ulcertive colitis colon: site for regultory T cell ction. Clin. Exp. Immunol. 151: Sphn TW nd Kuchrzlk T (2004). Modulting the intestinl immune system: the role of lymphotoxin nd GALT orgns. Gut 53: Sumid Y, Nkmur K, Knym K, Akiho H, et l. (2008). Preprtion of functionlly preserved CD4 + CD25 + high regultory T cells from leukpheresis products from ulcertive colitis ptients, pplicble to regultory T-cell trnsfer therpy. Cytotherpy 10: Thompson-Chgoyán OC, Mldondo J nd Gil A (2005). Aetiology of inflmmtory bowel disese (IBD): role of intestinl microbiot nd gut-ssocited lymphoid tissue immune response. Clin. Nutr. 24: Ufer M, Häsler R, Jcobs G, Henisch S, et l. (2009). Decresed sigmoidl ABCB1 (P-glycoprotein) expression in ulcertive colitis is ssocited with disese ctivity. Phrmcogenomics 10: Verbon A, Leemns JC, Weijer S, Florquin S, et l. (2002). Mice lcking the multidrug resistnce protein 1 hve trnsiently impired immune response during tuberculosis. Clin. Exp. Immunol. 130: Wsilewsk A, Zlewski G, Chyczewski L nd Zoch-Zwierz W (2007). MDR-1 gene polymorphisms nd clinicl course of steroid-responsive nephrotic syndrome in children. Peditr. Nephrol. 22:

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