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Erschienen in: Clinical Rheumatology 2/2016

01.02.2016 | Original Article

Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus

verfasst von: Amit Kansal, Deepak Tripathi, Mohit K. Rai, Vikas Agarwal

Erschienen in: Clinical Rheumatology | Ausgabe 2/2016

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Abstract

Corticosteroids (CS) are the mainstay of treatment in systemic lupus erythematosus (SLE) patients. However, some patients have poor response to CS treatment. Among the multiple mechanisms of CS resistance, overexpression of P-glycoprotein (P-gp) on peripheral blood lymphocytes (PBL) may be one of them as this result in efflux of CS from lymphocytes. Thus, we evaluated the role of P-gp protein on PBLs in patients with SLE in its response to CS therapy. SLE patients (n = 42) (fulfilling ACR revised criteria) who were naïve to CS and immunosuppressive drugs were enrolled. Disease activity was assessed using SLE disease activity index (SLEDAI) and expression, and function of P-gp was evaluated by flow cytometry at baseline and after 3 months of therapy with CS. At 3 months, patients with SLEDAI >4 and SLEDAI ≤4 were grouped as nonresponders and responders, respectively. P-gp expression was significantly increased on PBLs of SLE patients as compared to healthy controls (p < 0.001). P-gp expression and function correlated with SLEDAI (r = 0.49, p = 0.005; and r = 0.49, p = 0.001, respectively). P-gp expression and function were not different in responders and nonresponders at baseline. However, at 3 months of CS therapy, P-gp expression and function decreased in responders (p < 0.001 and p < 0.005, respectively), whereas in nonresponders, it remained unchanged. Persistent overexpression and activity of P-gp are associated with poor response to CS in CS naïve patients of SLE.
Literatur
1.
Zurück zum Zitat Wallace DJ (2010) Advances in drug therapy for systemic lupus erythematosus. BMC Med 29:77CrossRef Wallace DJ (2010) Advances in drug therapy for systemic lupus erythematosus. BMC Med 29:77CrossRef
2.
Zurück zum Zitat Franchimont DP, Chrousos GP (2008) Glucocorticoid Resistance in Inflammatory Diseases. In: Rey AD, Chrousos GP, Besedovsky HO (eds) The Hypothalamus–Pituitary–Adrenal Axis. Elsevier B.V, Amsterdam, Netherlands, pp 349–358 Franchimont DP, Chrousos GP (2008) Glucocorticoid Resistance in Inflammatory Diseases. In: Rey AD, Chrousos GP, Besedovsky HO (eds) The Hypothalamus–Pituitary–Adrenal Axis. Elsevier B.V, Amsterdam, Netherlands, pp 349–358
3.
Zurück zum Zitat Beck WT, Grogan TM, Willman CL, Cordon-Cardo C, Parham DM, Kuttesch JF et al (1996) Methods to detect P-glycoprotein-associated multidrug resistance in patients’ tumors: consensus recommendations. Cancer Res 56:3010–3020PubMed Beck WT, Grogan TM, Willman CL, Cordon-Cardo C, Parham DM, Kuttesch JF et al (1996) Methods to detect P-glycoprotein-associated multidrug resistance in patients’ tumors: consensus recommendations. Cancer Res 56:3010–3020PubMed
4.
Zurück zum Zitat Advani R, Visani G, Milligan D, Saba H, Tallman M, Rowe JM et al (1999) Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Adv Exp Med Biol 457:47–56CrossRefPubMed Advani R, Visani G, Milligan D, Saba H, Tallman M, Rowe JM et al (1999) Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Adv Exp Med Biol 457:47–56CrossRefPubMed
5.
Zurück zum Zitat List AF, Kopecky KJ, Willman CL, Head DR, Slovak ML, Douer D et al (2002) Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase. Blood 100:1910–1912PubMed List AF, Kopecky KJ, Willman CL, Head DR, Slovak ML, Douer D et al (2002) Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase. Blood 100:1910–1912PubMed
6.
Zurück zum Zitat Linn SC, Honkoop AH, Hoekman K, van der Valk P, Pinedo HM, Giaccone G (1996) p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer. Br J Cancer 74:63–68PubMedCentralCrossRefPubMed Linn SC, Honkoop AH, Hoekman K, van der Valk P, Pinedo HM, Giaccone G (1996) p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer. Br J Cancer 74:63–68PubMedCentralCrossRefPubMed
7.
Zurück zum Zitat Richaud-Patin Y, Soto-Vega E, Jakez-Ocampo J, Llorente L (2004) P-glycoprotein in autoimmune diseases. Autoimmun Rev 3:188–192CrossRefPubMed Richaud-Patin Y, Soto-Vega E, Jakez-Ocampo J, Llorente L (2004) P-glycoprotein in autoimmune diseases. Autoimmun Rev 3:188–192CrossRefPubMed
8.
Zurück zum Zitat Callaghan R, Crowley E, Potter S, Kerr ID (2008) P-glycoprotein: so many ways to turn it on. J Clin Pharmacol 48:365–378CrossRefPubMed Callaghan R, Crowley E, Potter S, Kerr ID (2008) P-glycoprotein: so many ways to turn it on. J Clin Pharmacol 48:365–378CrossRefPubMed
9.
Zurück zum Zitat Tsuruo T (1983) Reversal of acquired resistance to vinca alkaloids and anthracyclines antibiotics. Cancer Treat Rep 67:889–894PubMed Tsuruo T (1983) Reversal of acquired resistance to vinca alkaloids and anthracyclines antibiotics. Cancer Treat Rep 67:889–894PubMed
10.
Zurück zum Zitat Ueda K, Cardaralli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human “MDR-1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci U S A 84:3004–3008PubMedCentralCrossRefPubMed Ueda K, Cardaralli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human “MDR-1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci U S A 84:3004–3008PubMedCentralCrossRefPubMed
11.
Zurück zum Zitat Bourgeois S, Gruol DJ, Newby BR, Rajah FM (1993) Expression of an MDR gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Mol Endocrinol 7:840–851PubMed Bourgeois S, Gruol DJ, Newby BR, Rajah FM (1993) Expression of an MDR gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Mol Endocrinol 7:840–851PubMed
12.
Zurück zum Zitat Meijer OC, de Lange EC, Breimer DD, de Boer AG, Workel JO, de Kloet ER (1998) Penetration of dexamethasone into brain corticosteroid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139:1789–1793PubMed Meijer OC, de Lange EC, Breimer DD, de Boer AG, Workel JO, de Kloet ER (1998) Penetration of dexamethasone into brain corticosteroid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139:1789–1793PubMed
13.
Zurück zum Zitat Wasilewska AM, Zoch-Zwierz WM, Pietruczuk M (2006) Expression of P-glycoprotein in lymphocytes of children with nephrotic syndrome treated with glucocorticoids. Eur J Pediatr 165:839–844CrossRefPubMed Wasilewska AM, Zoch-Zwierz WM, Pietruczuk M (2006) Expression of P-glycoprotein in lymphocytes of children with nephrotic syndrome treated with glucocorticoids. Eur J Pediatr 165:839–844CrossRefPubMed
14.
Zurück zum Zitat Guiducci C, Gong M, Xu Z, Gill M et al (2010) TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465:937–941PubMedCentralCrossRefPubMed Guiducci C, Gong M, Xu Z, Gill M et al (2010) TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465:937–941PubMedCentralCrossRefPubMed
15.
Zurück zum Zitat Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 373:1905–1917CrossRefPubMed Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 373:1905–1917CrossRefPubMed
16.
Zurück zum Zitat Farrell RJ, Kelleher D (2003) Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 178:339–346CrossRefPubMed Farrell RJ, Kelleher D (2003) Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 178:339–346CrossRefPubMed
17.
Zurück zum Zitat Tsujimura S, Saito K, Nakayamada S, Tanaka Y (2010) Etanercept overcomes P-glycoprotein induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis. Mod Rheumatol 20:139–146CrossRefPubMed Tsujimura S, Saito K, Nakayamada S, Tanaka Y (2010) Etanercept overcomes P-glycoprotein induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis. Mod Rheumatol 20:139–146CrossRefPubMed
18.
Zurück zum Zitat Maillefert JF, Maynadie M, Tebib JG et al (1996) Expression of the multidrug resistance glycoprotein 170 in the peripheral blood lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes expressing glycoprotein 170 is increased in patients treated with prednisolone. Br J Rheumatol 35:430–435CrossRefPubMed Maillefert JF, Maynadie M, Tebib JG et al (1996) Expression of the multidrug resistance glycoprotein 170 in the peripheral blood lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes expressing glycoprotein 170 is increased in patients treated with prednisolone. Br J Rheumatol 35:430–435CrossRefPubMed
19.
Zurück zum Zitat Bradshaw DM, Arceci RJ (1998) Clinical relevance of transmembrane drug efflux as mechanism of multidrug resistance. J Clin Oncol 16:3674–3690PubMed Bradshaw DM, Arceci RJ (1998) Clinical relevance of transmembrane drug efflux as mechanism of multidrug resistance. J Clin Oncol 16:3674–3690PubMed
20.
Zurück zum Zitat Tan B, Piwnica-Worms D, Ratner L (2000) Multidrug resistance transporters and modulation. Curr Opin Oncol 12:450–458CrossRefPubMed Tan B, Piwnica-Worms D, Ratner L (2000) Multidrug resistance transporters and modulation. Curr Opin Oncol 12:450–458CrossRefPubMed
21.
Zurück zum Zitat Hirano T, Onda K, Toma T, Miyaoka M, Moriyasu F, Oka K (2004) MDR1 mRNA expressions in peripheral blood mononuclear cells of patients with ulcerative colitis in relation to glucocorticoid administration. J Clin Pharmacol 44:481–486CrossRefPubMed Hirano T, Onda K, Toma T, Miyaoka M, Moriyasu F, Oka K (2004) MDR1 mRNA expressions in peripheral blood mononuclear cells of patients with ulcerative colitis in relation to glucocorticoid administration. J Clin Pharmacol 44:481–486CrossRefPubMed
22.
Zurück zum Zitat Tsujimura S, Saito K, Nakayamada S, Nakano K, Tanaka Y (2005) Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheum 52:1676–1683CrossRefPubMed Tsujimura S, Saito K, Nakayamada S, Nakano K, Tanaka Y (2005) Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheum 52:1676–1683CrossRefPubMed
23.
Zurück zum Zitat Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 40:1725CrossRefPubMed Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 40:1725CrossRefPubMed
24.
Zurück zum Zitat Jafar T, Prasad N, Agarwal V, Mahdi A, Gupta A, Sharma RK, Negi MP, Agrawal S (2011) MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant 26:3968–3974CrossRefPubMed Jafar T, Prasad N, Agarwal V, Mahdi A, Gupta A, Sharma RK, Negi MP, Agrawal S (2011) MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant 26:3968–3974CrossRefPubMed
25.
Zurück zum Zitat Gonzalez TP, Mucenic T, Brenol JC, Xavier RM, Schiengold M, Chies JA (2008) ABCB1 C1236T, G2677T/A and C3435T polymorphisms in systemic lupus erythematosus patients. Braz J Med Biol Res 41:769–772CrossRefPubMed Gonzalez TP, Mucenic T, Brenol JC, Xavier RM, Schiengold M, Chies JA (2008) ABCB1 C1236T, G2677T/A and C3435T polymorphisms in systemic lupus erythematosus patients. Braz J Med Biol Res 41:769–772CrossRefPubMed
26.
Zurück zum Zitat Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199CrossRefPubMed Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199CrossRefPubMed
27.
Zurück zum Zitat Siegmund W, Ludwig K, Giessmann T, Dazert P, Schroeder E, Sperker B et al (2002) The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 72:572–583CrossRefPubMed Siegmund W, Ludwig K, Giessmann T, Dazert P, Schroeder E, Sperker B et al (2002) The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 72:572–583CrossRefPubMed
28.
Zurück zum Zitat Baker EK, Johnstone RW, Zaleberg JR et al (2005) Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs. Oncogene 24:8061–8075CrossRefPubMed Baker EK, Johnstone RW, Zaleberg JR et al (2005) Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs. Oncogene 24:8061–8075CrossRefPubMed
29.
Zurück zum Zitat Huang C, Peiguo CAO, Zhaoxia XIE (2009) Relation of promoter methylation of mdr-1 gene and histone acetylation status with multidrug resistance in MCF-7/Adr cells. J Cent South Univ (Med Sci) 34:369–374 Huang C, Peiguo CAO, Zhaoxia XIE (2009) Relation of promoter methylation of mdr-1 gene and histone acetylation status with multidrug resistance in MCF-7/Adr cells. J Cent South Univ (Med Sci) 34:369–374
30.
Zurück zum Zitat Mishra N, Reilly CM, Brown DR (2003) Phil Ruiz and Gary S Gilkeson. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest 111:539–552PubMedCentralCrossRefPubMed Mishra N, Reilly CM, Brown DR (2003) Phil Ruiz and Gary S Gilkeson. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest 111:539–552PubMedCentralCrossRefPubMed
31.
Zurück zum Zitat Kelly E, Won A, Refaeli Y, van Parijs L (2002) IL-2 and related cytokines can promote T cell survival by activating AKT. J Immunol 168:597–603CrossRefPubMed Kelly E, Won A, Refaeli Y, van Parijs L (2002) IL-2 and related cytokines can promote T cell survival by activating AKT. J Immunol 168:597–603CrossRefPubMed
32.
Zurück zum Zitat Luxembourg AT, Cooper NR (1994) T cell-dependent, B cell-activating properties of antibody-coated small latex beads: a new model for B cell activation. J Immunol 153:604–614PubMed Luxembourg AT, Cooper NR (1994) T cell-dependent, B cell-activating properties of antibody-coated small latex beads: a new model for B cell activation. J Immunol 153:604–614PubMed
33.
Zurück zum Zitat Tsujimura S, Saito K, Nakayamada S, Nakano K, Tsukada J, Kohno K et al (2004) Transcriptional regulation of multidrug resis-tance-1 gene by interleukin-2 in lymphocytes. Genes Cells 9:1265–1273CrossRefPubMed Tsujimura S, Saito K, Nakayamada S, Nakano K, Tsukada J, Kohno K et al (2004) Transcriptional regulation of multidrug resis-tance-1 gene by interleukin-2 in lymphocytes. Genes Cells 9:1265–1273CrossRefPubMed
34.
Zurück zum Zitat Zhang B, Shi Y, Lei TC (2012) Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control. Exp Ther Med 4:705–710PubMedCentralPubMed Zhang B, Shi Y, Lei TC (2012) Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control. Exp Ther Med 4:705–710PubMedCentralPubMed
35.
Zurück zum Zitat Miyasaka N, Kawai S, Hashimoto H (2009) Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol 19:606–615CrossRefPubMed Miyasaka N, Kawai S, Hashimoto H (2009) Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol 19:606–615CrossRefPubMed
36.
Zurück zum Zitat Uchino A, Tsukamoto H, Nakashima H, Yoshizawa S, Furugo I et al (2010) Tacrolimus is effective for lupus nephritis patients with persistent proteinuria. Clin Exp Rheumatol 28:6–12PubMed Uchino A, Tsukamoto H, Nakashima H, Yoshizawa S, Furugo I et al (2010) Tacrolimus is effective for lupus nephritis patients with persistent proteinuria. Clin Exp Rheumatol 28:6–12PubMed
37.
Zurück zum Zitat Wang S, Li X, Qu L, Wang R, Chen Y, Li Q, He X, Zhang X, Wang H, Wu J, Xu Y, Chen J (2012) Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: a non-randomized prospective cohort study. Lupus 21:1025–1035CrossRefPubMed Wang S, Li X, Qu L, Wang R, Chen Y, Li Q, He X, Zhang X, Wang H, Wu J, Xu Y, Chen J (2012) Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: a non-randomized prospective cohort study. Lupus 21:1025–1035CrossRefPubMed
38.
Zurück zum Zitat Chen W, Liu Q, Chen W, Tang X, Fu P et al (2012) Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. Lupus 21:944–952CrossRefPubMed Chen W, Liu Q, Chen W, Tang X, Fu P et al (2012) Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. Lupus 21:944–952CrossRefPubMed
39.
Zurück zum Zitat Tanaka H, Watanabe S, Aizawa-Yashiro T, Oki E, Kumagai N, Tsuruga K, Ito E (2013) Long-term tacrolimus-based immunosuppressive treatment for young patients with lupus nephritis: a prospective study in daily clinical practice. Nephron Clin Pract 121:c165–c173CrossRef Tanaka H, Watanabe S, Aizawa-Yashiro T, Oki E, Kumagai N, Tsuruga K, Ito E (2013) Long-term tacrolimus-based immunosuppressive treatment for young patients with lupus nephritis: a prospective study in daily clinical practice. Nephron Clin Pract 121:c165–c173CrossRef
40.
Zurück zum Zitat Deng J, Huo D, Wu Q, Yang Z, Liao Y (2012) A meta-analysis of randomized controlled trials comparing tacrolimus with intravenous cyclophosphamide in the induction treatment for lupus nephritis. Tohoku J Exp Med 227:281–288CrossRefPubMed Deng J, Huo D, Wu Q, Yang Z, Liao Y (2012) A meta-analysis of randomized controlled trials comparing tacrolimus with intravenous cyclophosphamide in the induction treatment for lupus nephritis. Tohoku J Exp Med 227:281–288CrossRefPubMed
41.
Zurück zum Zitat Fei Y, Wu Q, Zhang W, Chen H, Hou Y et al (2013) Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. Clin Exp Rheumatol 31:62–68PubMed Fei Y, Wu Q, Zhang W, Chen H, Hou Y et al (2013) Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. Clin Exp Rheumatol 31:62–68PubMed
42.
Zurück zum Zitat Radha R, Lina K, Kelly MK, Djuretic IM, Carlson TJ, Quintero MA, McCauley JL, Abreu MT, Derya U, Sundrud MS (2014) Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211:89–104CrossRef Radha R, Lina K, Kelly MK, Djuretic IM, Carlson TJ, Quintero MA, McCauley JL, Abreu MT, Derya U, Sundrud MS (2014) Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211:89–104CrossRef
43.
Zurück zum Zitat Shah K, Lee W-W, Lee S-H, Kim SH, Kang SW, Craft J, Kang I (2010) Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther 12:R53PubMedCentralCrossRefPubMed Shah K, Lee W-W, Lee S-H, Kim SH, Kang SW, Craft J, Kang I (2010) Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther 12:R53PubMedCentralCrossRefPubMed
Metadaten
Titel
Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus
verfasst von
Amit Kansal
Deepak Tripathi
Mohit K. Rai
Vikas Agarwal
Publikationsdatum
01.02.2016
Verlag
Springer London
Erschienen in
Clinical Rheumatology / Ausgabe 2/2016
Print ISSN: 0770-3198
Elektronische ISSN: 1434-9949
DOI
https://doi.org/10.1007/s10067-015-3079-7

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