메뉴 건너뛰기




Volumn 114, Issue 3, 1998, Pages 468-476

Imbalances in serum proinflammatory cytokines and their soluble receptors: A putative role in the progression of idiopathic IgA nephropathy (IgAN) and Henoch-Schonlein purpura nephritis, and a potential target of immunoglobulin therapy?

Author keywords

Henoch Schonlein syndrome; IgA nephropathy; Immunoglobulin therapy; TNF soluble receptors; Tumour necrosis factor alpha

Indexed keywords

IMMUNOGLOBULIN; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR;

EID: 0031737511     PISSN: 00099104     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2249.1998.00745.x     Document Type: Article
Times cited : (62)

References (54)
  • 1
    • 0028934504 scopus 로고
    • IgA nephropathy
    • Galla J. IgA nephropathy. Kidney Int 1995; 47:377-87.
    • (1995) Kidney Int , vol.47 , pp. 377-387
    • Galla, J.1
  • 2
    • 0028281556 scopus 로고
    • High-dose immunoglobulin therapy for severe IgA nephropathy and Henoch-Schönlein purpura
    • Rostoker G, Desvaux-Belghiti D, Pilatte Y et al. High-dose immunoglobulin therapy for severe IgA nephropathy and Henoch-Schönlein purpura. Ann Intern Med 1994; 120:476-84.
    • (1994) Ann Intern Med , vol.120 , pp. 476-484
    • Rostoker, G.1    Desvaux-Belghiti, D.2    Pilatte, Y.3
  • 3
    • 0028955139 scopus 로고
    • Immunomodulation with low-dose immunoglobulins for moderate IgA nephropathy and Henoch-Schönlein purpura: Preliminary results of a prospective uncontrolled trial
    • Rostoker G, Desvaux-Belghiti D, Pilatte Y et al. Immunomodulation with low-dose immunoglobulins for moderate IgA nephropathy and Henoch-Schönlein purpura: preliminary results of a prospective uncontrolled trial. Nephron 1995; 69:327-34.
    • (1995) Nephron , vol.69 , pp. 327-334
    • Rostoker, G.1    Desvaux-Belghiti, D.2    Pilatte, Y.3
  • 5
    • 0002894257 scopus 로고
    • Hypothetic and established action mechanisms of therapy with immunoglobulin G
    • Imbach P, ed. London: Academic Press
    • Nydegger U. Hypothetic and established action mechanisms of therapy with immunoglobulin G. In: Imbach P, ed. Immunotherapy with intravenous immunoglobulins. London: Academic Press, 1991:27-36.
    • (1991) Immunotherapy with Intravenous Immunoglobulins , pp. 27-36
    • Nydegger, U.1
  • 6
    • 0025220981 scopus 로고
    • Human intravenous immunoglobulin modulates monokine production in vitro
    • Andersson JP, Andersson UG. Human intravenous immunoglobulin modulates monokine production in vitro. Immunology 1990; 71:372-6.
    • (1990) Immunology , vol.71 , pp. 372-376
    • Andersson, J.P.1    Andersson, U.G.2
  • 7
    • 0005151320 scopus 로고
    • IgA related glomerulopathies
    • Oliviera D, ed. Cambridge: University Press
    • Oliviera D. IgA related glomerulopathies. In: Oliviera D, ed. Immunological aspects of renal disease. Cambridge: University Press, 1992:87-113.
    • (1992) Immunological Aspects of Renal Disease , pp. 87-113
    • Oliviera, D.1
  • 8
    • 0026748973 scopus 로고
    • Extrarenal cytokines modulate the glomerular response to IgA immune complexes
    • Montinaro V, Hevey K, Aventaggiato L et al. Extrarenal cytokines modulate the glomerular response to IgA immune complexes. Kidney Int 1992; 42:341-53.
    • (1992) Kidney Int , vol.42 , pp. 341-353
    • Montinaro, V.1    Hevey, K.2    Aventaggiato, L.3
  • 9
    • 0028202508 scopus 로고
    • The potential role of inflammatory and fibrogenic cytokines in the glomerular diseases
    • Ortiz A, Gomez-Chiarri M, Alonso J et al. The potential role of inflammatory and fibrogenic cytokines in the glomerular diseases. J Lipid Med Cell Signalling 1994; 9:55-74.
    • (1994) J Lipid Med Cell Signalling , vol.9 , pp. 55-74
    • Ortiz, A.1    Gomez-Chiarri, M.2    Alonso, J.3
  • 10
    • 0020072141 scopus 로고
    • IgA nephropathy, morphologic predictors of progressive renal disease
    • Lee K, Rao V, Franklin W et al. IgA nephropathy, morphologic predictors of progressive renal disease. Hum Pathol 1982; 13:314-22.
    • (1982) Hum Pathol , vol.13 , pp. 314-322
    • Lee, K.1    Rao, V.2    Franklin, W.3
  • 11
    • 0016916438 scopus 로고
    • Prediction of creatinine clearance from the serum creatinine
    • Cockroft D, Gault M. Prediction of creatinine clearance from the serum creatinine. Nephron 1976; 16:31-41.
    • (1976) Nephron , vol.16 , pp. 31-41
    • Cockroft, D.1    Gault, M.2
  • 12
    • 0028595604 scopus 로고
    • Cytokine measurements and interpretation of cytokine assays in human disease
    • Whiteside T. Cytokine measurements and interpretation of cytokine assays in human disease. J Clin Immunol 1994; 14:327-39.
    • (1994) J Clin Immunol , vol.14 , pp. 327-339
    • Whiteside, T.1
  • 13
    • 0000060928 scopus 로고
    • Immune interferon: A pleiotropic lymphokine with multiple effects
    • Trinchieri G, Perussia B. Immune interferon: a pleiotropic lymphokine with multiple effects. Immunol Today 1985; 6:131-6.
    • (1985) Immunol Today , vol.6 , pp. 131-136
    • Trinchieri, G.1    Perussia, B.2
  • 14
    • 0028983572 scopus 로고
    • Balance between IL1β, TNFα and their specific inhibitors in chronic renal failure and maintenance dialysis
    • Descamps-Latscha B, Herbelin A, Thu Nguyen A et al. Balance between IL1β, TNFα and their specific inhibitors in chronic renal failure and maintenance dialysis. J Immunol 1995; 154:882-92.
    • (1995) J Immunol , vol.154 , pp. 882-892
    • Descamps-Latscha, B.1    Herbelin, A.2    Thu Nguyen, A.3
  • 15
    • 0025801687 scopus 로고
    • Elevated circulating levels of interleukin-6 in patients with chronic renal failure
    • Herbelin A, Urena P, Thu Nguyen A et al. Elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 1991; 39:954-60.
    • (1991) Kidney Int , vol.39 , pp. 954-960
    • Herbelin, A.1    Urena, P.2    Thu Nguyen, A.3
  • 16
    • 0028574382 scopus 로고
    • Interleukin 1, tumor necrosis factor and their specific inhibitors
    • Dayer JM, Burger D. Interleukin 1, tumor necrosis factor and their specific inhibitors. Eur Cytokine Netw 1994; 5:563-71.
    • (1994) Eur Cytokine Netw , vol.5 , pp. 563-571
    • Dayer, J.M.1    Burger, D.2
  • 17
    • 0028150888 scopus 로고
    • Plasma levels of tumor necrosis factor and soluble TNF receptors in kidney transplant recipients
    • Dörge SE, Roux-Lombard P, Daher JM et al. Plasma levels of tumor necrosis factor and soluble TNF receptors in kidney transplant recipients. Transplantation 1994; 58:1000-8.
    • (1994) Transplantation , vol.58 , pp. 1000-1008
    • Dörge, S.E.1    Roux-Lombard, P.2    Daher, J.M.3
  • 18
    • 0023230261 scopus 로고
    • Composition of IgA immune complexes precipitated with polyethylene glycol. A method for isolation and analysis of immune complexes
    • Imai H, Chen A, Wyatt R et al. Composition of IgA immune complexes precipitated with polyethylene glycol. A method for isolation and analysis of immune complexes. J Immunol Methods 1987; 103:239-15.
    • (1987) J Immunol Methods , vol.103 , pp. 239-315
    • Imai, H.1    Chen, A.2    Wyatt, R.3
  • 19
    • 0026457788 scopus 로고
    • Secretory IgA are elevated in both saliva and serum of patients with various types of primary glomerulonephritis
    • Rostoker G, Terzidis H, Petit-Phar M et al. Secretory IgA are elevated in both saliva and serum of patients with various types of primary glomerulonephritis. Clin Exp Immunol 1992; 90:305-11.
    • (1992) Clin Exp Immunol , vol.90 , pp. 305-311
    • Rostoker, G.1    Terzidis, H.2    Petit-Phar, M.3
  • 20
    • 0024384033 scopus 로고
    • Specificity and association constants of 33 monoclonal antibodies to human IgA epitopes
    • Reimer C, Philipps D, Aloisio C et al. Specificity and association constants of 33 monoclonal antibodies to human IgA epitopes. Immunol Letters 1989; 21:209-16.
    • (1989) Immunol Letters , vol.21 , pp. 209-216
    • Reimer, C.1    Philipps, D.2    Aloisio, C.3
  • 21
    • 0024041230 scopus 로고
    • Circulating complexes containing IgA fibronectin in patients with primary IgA nephropathy
    • Cederholm B, Wieslander J, Bygren Heinegard D. Circulating complexes containing IgA fibronectin in patients with primary IgA nephropathy. Proc Natl Acad Sci USA 1988; 85:4865-8.
    • (1988) Proc Natl Acad Sci USA , vol.85 , pp. 4865-4868
    • Cederholm, B.1    Wieslander, J.2    Bygren Heinegard, D.3
  • 23
    • 0027979377 scopus 로고
    • Effect of plasma protein absorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome
    • Dantal J, Bigot E, Bogers W et al. Effect of plasma protein absorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 1994; 330:7-14.
    • (1994) N Engl J Med , vol.330 , pp. 7-14
    • Dantal, J.1    Bigot, E.2    Bogers, W.3
  • 24
    • 0026708465 scopus 로고
    • Imbalance between tumor necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia
    • Girardin E, Roux-Lombard P, Grau G et al. Imbalance between tumor necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. Immunology 1992; 76:20-23.
    • (1992) Immunology , vol.76 , pp. 20-23
    • Girardin, E.1    Roux-Lombard, P.2    Grau, G.3
  • 25
    • 0030022090 scopus 로고    scopus 로고
    • Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome
    • Gherardi R, Belec L, Soubrier M et al. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. Blood 1996; 87:1458-65.
    • (1996) Blood , vol.87 , pp. 1458-1465
    • Gherardi, R.1    Belec, L.2    Soubrier, M.3
  • 26
    • 0024513550 scopus 로고
    • Tumor necrosis factor induces glomerular damage in rabbits
    • Bertani T, Abbate M, Zoja C et al. Tumor necrosis factor induces glomerular damage in rabbits. Am J Pathol 1989; 134:419-30.
    • (1989) Am J Pathol , vol.134 , pp. 419-430
    • Bertani, T.1    Abbate, M.2    Zoja, C.3
  • 27
    • 0028048995 scopus 로고
    • Effects of tumor necrosis α and interleukin 1β on the proliferation of cultured glomerular epithelial cells
    • Yanagisawa M, Imai H, Fukushima Y et al. Effects of tumor necrosis α and interleukin 1β on the proliferation of cultured glomerular epithelial cells. Virchows Arch 1994; 424:581-6.
    • (1994) Virchows Arch , vol.424 , pp. 581-586
    • Yanagisawa, M.1    Imai, H.2    Fukushima, Y.3
  • 28
    • 0026376307 scopus 로고
    • Mesangial cell turnover: Effect of heparin and peptide growth factors
    • Striker L, Peten E, Elliot S et al. Mesangial cell turnover: effect of heparin and peptide growth factors. Lab Invest 1991; 64:446-56.
    • (1991) Lab Invest , vol.64 , pp. 446-456
    • Striker, L.1    Peten, E.2    Elliot, S.3
  • 29
    • 0024565924 scopus 로고
    • Modulation of antibody mediated glomerular injury in vivo by bacterial liposaccharide, tumor necrosis factor and IL1
    • Tomosugi N, Cashman S, Pusey C et al. Modulation of antibody mediated glomerular injury in vivo by bacterial liposaccharide, tumor necrosis factor and IL1. J Immunol 1989; 142:3083-90.
    • (1989) J Immunol , vol.142 , pp. 3083-3090
    • Tomosugi, N.1    Cashman, S.2    Pusey, C.3
  • 30
    • 0025202086 scopus 로고
    • Effect of leukocyte stimulation on rabbit immune complex glomerulonephritis
    • Camussi G, Tetta C, Bussolino F et al. Effect of leukocyte stimulation on rabbit immune complex glomerulonephritis. Kidney Int 1990; 38:1047-55.
    • (1990) Kidney Int , vol.38 , pp. 1047-1055
    • Camussi, G.1    Tetta, C.2    Bussolino, F.3
  • 31
    • 0025818245 scopus 로고
    • Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury
    • Hruby Z, Shirota K, Jothy S, Lowry R. Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury. Kidney Int 1991; 40:43-51.
    • (1991) Kidney Int , vol.40 , pp. 43-51
    • Hruby, Z.1    Shirota, K.2    Jothy, S.3    Lowry, R.4
  • 32
    • 0028827486 scopus 로고
    • Modulation of antibody-mediated glomerular injury in vivo by IL1-ra, soluble IL1 receptor and soluble TNF receptor
    • Karkar A, Tam F, Steinkasserer A et al. Modulation of antibody-mediated glomerular injury in vivo by IL1-ra, soluble IL1 receptor and soluble TNF receptor. Kidney Int 1995; 48:1738-46.
    • (1995) Kidney Int , vol.48 , pp. 1738-1746
    • Karkar, A.1    Tam, F.2    Steinkasserer, A.3
  • 33
    • 0027432377 scopus 로고
    • In situ expression of cytokines in IgA nephritis
    • Yoshioka K, Takemura T, Murakami K et al. In situ expression of cytokines in IgA nephritis. Kidney Int 1993; 44:825-33.
    • (1993) Kidney Int , vol.44 , pp. 825-833
    • Yoshioka, K.1    Takemura, T.2    Murakami, K.3
  • 34
    • 0027236911 scopus 로고
    • Increased release of tumor necrosis factor α by monocytes from patients with glomerulonephritis
    • Matsumoto K. Increased release of tumor necrosis factor α by monocytes from patients with glomerulonephritis. Clin Nephrol 1993; 40:148-54.
    • (1993) Clin Nephrol , vol.40 , pp. 148-154
    • Matsumoto, K.1
  • 35
    • 0026798797 scopus 로고
    • Kawasaki disease differs from anaphylactoid purpura and measles with regard, to tumour necrosis factor alpha and interleukin 6 in serum
    • Furukawa S, Matsubara T, Yone K et al. Kawasaki disease differs from anaphylactoid purpura and measles with regard, to tumour necrosis factor alpha and interleukin 6 in serum. Eur J Pediatr 1992; 151:44-47.
    • (1992) Eur J Pediatr , vol.151 , pp. 44-47
    • Furukawa, S.1    Matsubara, T.2    Yone, K.3
  • 36
    • 0029744259 scopus 로고    scopus 로고
    • Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Schönlein-Henoch purpura
    • Tsai-Hung W, Shiu-Chuan W, Tung-Po H et al. Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Schönlein-Henoch purpura. Nephron 1996; 74:79-88.
    • (1996) Nephron , vol.74 , pp. 79-88
    • Tsai-Hung, W.1    Shiu-Chuan, W.2    Tung-Po, H.3
  • 37
    • 0030857676 scopus 로고    scopus 로고
    • Glomerular ICAM-1 expression related to circulating TNF-α in human glomerulonephritis
    • Yokohama H, Takaeda M, Wada T et al. Glomerular ICAM-1 expression related to circulating TNF-α in human glomerulonephritis. Nephron 1997; 76:425-33.
    • (1997) Nephron , vol.76 , pp. 425-433
    • Yokohama, H.1    Takaeda, M.2    Wada, T.3
  • 38
    • 0028293458 scopus 로고
    • Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease: Up regulation of T cell proliferation and down-regulation of tumor necrosis α secretion
    • Achiron A, Margalit R, Hershkovitz R et al. Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease: up regulation of T cell proliferation and down-regulation of tumor necrosis α secretion. J Clin Invest 1994; 93:6005.
    • (1994) J Clin Invest , vol.93 , pp. 6005
    • Achiron, A.1    Margalit, R.2    Hershkovitz, R.3
  • 39
    • 0028024881 scopus 로고
    • Release of cytokines, soluble cytokine receptors and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo
    • Aukrust P, Froloand S, Liabakk N et al. Release of cytokines, soluble cytokine receptors and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo. Blood 1994; 84:2136-43.
    • (1994) Blood , vol.84 , pp. 2136-2143
    • Aukrust, P.1    Froloand, S.2    Liabakk, N.3
  • 40
    • 0028814278 scopus 로고
    • Balance of IL1 receptor antagonist/IL1β in rheumatoid synovium and its regulation by IL4 and IL10
    • Chomarat P, Vannier E, Dechanet J et al. Balance of IL1 receptor antagonist/IL1β in rheumatoid synovium and its regulation by IL4 and IL10. J Immunol 1995; 154:1432-9.
    • (1995) J Immunol , vol.154 , pp. 1432-1439
    • Chomarat, P.1    Vannier, E.2    Dechanet, J.3
  • 41
    • 0027247586 scopus 로고
    • Suppression of experimental crescentic glomerulonephritis by the interleukin 1 receptor antagonist
    • Lan H, Nikolic-Paterson D, Zarama M et al. Suppression of experimental crescentic glomerulonephritis by the interleukin 1 receptor antagonist. Kidney Int 1993; 43:479-85.
    • (1993) Kidney Int , vol.43 , pp. 479-485
    • Lan, H.1    Nikolic-Paterson, D.2    Zarama, M.3
  • 42
    • 0026411105 scopus 로고
    • Interleukin-1 production by monocytes from patients with glomerulonephritis after stimulation in vitro with soluble immune complexes
    • Matsumoto K. Interleukin-1 production by monocytes from patients with glomerulonephritis after stimulation in vitro with soluble immune complexes. Clin Nephrol 1991; 36:267-73.
    • (1991) Clin Nephrol , vol.36 , pp. 267-273
    • Matsumoto, K.1
  • 44
    • 0024805715 scopus 로고
    • Involvement of IL6 in mesangial proliferative glomerulonephritis
    • Horii Y, Muraguchi A, Iwano M et al. Involvement of IL6 in mesangial proliferative glomerulonephritis. J Immunol 1989; 143:3949-55.
    • (1989) J Immunol , vol.143 , pp. 3949-3955
    • Horii, Y.1    Muraguchi, A.2    Iwano, M.3
  • 45
    • 0025934334 scopus 로고
    • Urinary IL6: A marker for mesangial proliferative glomerulonephritis?
    • Gordon C, Richards N, Howie A et al. Urinary IL6: a marker for mesangial proliferative glomerulonephritis? Clin Exp Immunol 1991; 86:145-9.
    • (1991) Clin Exp Immunol , vol.86 , pp. 145-149
    • Gordon, C.1    Richards, N.2    Howie, A.3
  • 46
    • 0027524861 scopus 로고
    • Increased interleukin 6 mRNA expression by peripheral blood T cells from patients with IgA nephropathy
    • Nakamura T, Ebihara I, Takahashi T et al. Increased interleukin 6 mRNA expression by peripheral blood T cells from patients with IgA nephropathy. Autoimmunity 1993; 15:171-9.
    • (1993) Autoimmunity , vol.15 , pp. 171-179
    • Nakamura, T.1    Ebihara, I.2    Takahashi, T.3
  • 47
    • 0027363250 scopus 로고
    • Binding of cytokines to pharmaceutically prepared human immunoglobulin
    • Svenson M, Bagge Hansen M, Bendtzen K. Binding of cytokines to pharmaceutically prepared human immunoglobulin. J Clin Invest 1993; 92:2533-9.
    • (1993) J Clin Invest , vol.92 , pp. 2533-2539
    • Svenson, M.1    Bagge Hansen, M.2    Bendtzen, K.3
  • 48
    • 0026739444 scopus 로고
    • Intraglomerular expression of MHC class II and KI-67 antigens and serum γ interferon levels in IgA nephropatby
    • Yokoyama H, Takaeda M, Wada T et al. Intraglomerular expression of MHC class II and KI-67 antigens and serum γ interferon levels in IgA nephropatby. Nephron 1992; 62:169-75.
    • (1992) Nephron , vol.62 , pp. 169-175
    • Yokoyama, H.1    Takaeda, M.2    Wada, T.3
  • 49
    • 0028356942 scopus 로고
    • Experimental IgA nephropathy: Enhanced deposition of glomerular IgA immune complex in proteinuric state
    • Chen A, Ding SL, Sheu LF et al. Experimental IgA nephropathy: enhanced deposition of glomerular IgA immune complex in proteinuric state. Lab Invest 1994; 70:639-47.
    • (1994) Lab Invest , vol.70 , pp. 639-647
    • Chen, A.1    Ding, S.L.2    Sheu, L.F.3
  • 50
    • 0025938954 scopus 로고
    • Serum IgA-fibronectin aggregates in patients with IgA nephropathy and Henoch-Schönlein purpura: Diagnostic value and pathogenic implications
    • Jeannette C, Wieslander J, Tuttle et al. Serum IgA-fibronectin aggregates in patients with IgA nephropathy and Henoch-Schönlein purpura: diagnostic value and pathogenic implications. Am J Kidney Dis 1991; 18:466-71.
    • (1991) Am J Kidney Dis , vol.18 , pp. 466-471
    • Jeannette, C.1    Wieslander, J.2    Tuttle3
  • 51
    • 0023578484 scopus 로고
    • The role of fibronectin on the clearance and tissue uptake of antigens and immune complexes in rats
    • Cosio F, Bakaletz A. The role of fibronectin on the clearance and tissue uptake of antigens and immune complexes in rats. J Clin Invest 1987; 80:1270-9.
    • (1987) J Clin Invest , vol.80 , pp. 1270-1279
    • Cosio, F.1    Bakaletz, A.2
  • 52
    • 0028083224 scopus 로고
    • Synthetic fibronectin peptides suppress arthritis in rats by interrupting leucocyte adhesion and recruitment
    • Wahl S, Allen J, Hines H et al. Synthetic fibronectin peptides suppress arthritis in rats by interrupting leucocyte adhesion and recruitment. J Clin Invest 1994; 94:655-62.
    • (1994) J Clin Invest , vol.94 , pp. 655-662
    • Wahl, S.1    Allen, J.2    Hines, H.3
  • 53
    • 0028941306 scopus 로고
    • Neutralizing inflammatory cytokines in nephritis
    • Wardle BN. Neutralizing inflammatory cytokines in nephritis. Nephron 1995; 69:223-7.
    • (1995) Nephron , vol.69 , pp. 223-227
    • Wardle, B.N.1
  • 54
    • 0028942726 scopus 로고
    • Is there a role for specific anti-TNF strategies in glomerular diseases?
    • Ortiz A, Egido J. Is there a role for specific anti-TNF strategies in glomerular diseases? Nephrol Dial Transplant 1995; 10:309-11.
    • (1995) Nephrol Dial Transplant , vol.10 , pp. 309-311
    • Ortiz, A.1    Egido, J.2


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.