MODULATION OF ANTIBODY-MEDIATED GLOMERULAR INJURY IN-VIVO BY IL-1RA, SOLUBLE IL-1 RECEPTOR, AND SOLUBLE TNF RECEPTOR

被引:67
作者
KARKAR, AM
TAM, FWK
STEINKASSERER, A
KURRLE, R
LANGNER, K
SCALLON, BJ
MEAGER, A
REES, AJ
机构
[1] DEPT BIOCHEM, MRC, IMMUNOCHEM UNIT, OXFORD, ENGLAND
[2] BEHRINGWERKE AG, RES LABS, W-3550 MARBURG, GERMANY
[3] NATL INST BIOL STAND & CONTROLS, POTTERS BAR EN6 3QG, HERTS, ENGLAND
[4] CENTOCOR INC, MALVERN, PA 19355 USA
基金
英国医学研究理事会;
关键词
D O I
10.1038/ki.1995.472
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
The severity of glomerular injury in the heterologous phase of NTN is dependent on proinflammatory cytokines including TNF alpha and IL-1 beta, and can be enhanced by LPS. We have previously shown that passive immunization against IL-1 beta and TNF partialy abrogated the LPS effect in this model. In the present work, we have assessed the effects on glomerular injury of blocking the binding of IL-1 to its receptor by rh IL-1 receptor antagonist (IL-1ra) and by neutralizing IL-1 and TNF with rm soluble IL-1 receptor type1 (sIL-1Rt1) and rh sTNF receptor (sTNFr p55), respectively. Pretreatment with either IL-1ra, sIL-1Rt1, or sTNFr partially abrogated the effects of LPS and reduced albumin excretion from 45 +/- 8, 66 +/- 9, and 101 +/- 17 mg/24 hr to 13 +/- 4 (P < 0.02), 14 +/- 4 (P < 0.001), and 21 +/- 7 mg/24 hr (P < 0.001), respectively. Similarly, these inhibitors reduced the prevalence of glomerular capillary thrombi and the intensity of glomerular neutrophil infiltration. Glomerular thrombosis was reduced from 18 +/- 3%, 28 +/- 5%, and 25 +/- 7% to 3 +/- 2% (P < 0.002), 6 +/- 2% (P < 0.001), and 3 +/- 2 (P < 0.001), respectively, and glomerular neutrophil infiltration was reduced from 46 +/- 3, 54 +/- 2, and 59 +/- 8 to 19 +/- 2 (P < 0.001), 25 +/- 2 (P < 0.001), and 28 +/- 2 neutrophils/50 glomeruli in section, respectively. Coadministration of both soluble receptors of IL-1 and TNF caused a further decrease in glomerular injury. The protective effect was also noticed at four hours after induction of nephritis, and even when these inhibitors were administered after the LPS injection and at the same time of induction of nephritis. All three treatments reduced circulating TNF concentration (down to 20%, 34%, and 0%, respectively) but without detectable glomerular TNF gene expression. Glomerular IL-1 beta mRNA levels were also reduced by 41%, 53%, and 67%, respectively, when assessed by densitometric analysis of Northern blots. In contrast, the glomerular expression of IL-1ra was not affected by its exogenous administration but was mildly reduced by sIL-1Rt1 and sTNFr, which demonstrates the potential role for host derived IL-1ra as an endogenous negative feedback mediator in the glomerulus. These results confirm the direct involvement of IL-1 and TNF in LPS-enhanced hNTN and demonstrate the potency of these inhibitors in modulating injury even when administered after LPS and at time of induction of nephritis. They were more specific and effective than passive immunization with polyclonal antibodies, and this demonstrates their potential usefulness in the management of nephritis.
引用
收藏
页码:1738 / 1746
页数:9
相关论文
共 67 条
[1]   INTERLEUKIN-1 (IL-1) RECEPTOR ANTAGONIST PREVENTS STAPHYLOCOCCUS-EPIDERMIDIS-INDUCED HYPOTENSION AND REDUCES CIRCULATING LEVELS OF TUMOR-NECROSIS-FACTOR AND IL-1-BETA IN RABBITS [J].
AIURA, K ;
GELFAND, JA ;
BURKE, JF ;
THOMPSON, RC ;
DINARELLO, CA .
INFECTION AND IMMUNITY, 1993, 61 (08) :3342-3350
[2]   A RECOMBINANT HUMAN RECEPTOR ANTAGONIST TO INTERLEUKIN-1 IMPROVES SURVIVAL AFTER LETHAL ENDOTOXEMIA IN MICE [J].
ALEXANDER, HR ;
DOHERTY, GM ;
BURESH, CM ;
VENZON, DJ ;
NORTON, JA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 173 (04) :1029-1032
[3]  
AREND WP, 1991, J IMMUNOL, V147, P1530
[4]   CONTROL OF ESTABLISHED EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS BY INHIBITION OF TUMOR-NECROSIS-FACTOR (TNF) ACTIVITY WITHIN THE CENTRAL-NERVOUS-SYSTEM USING MONOCLONAL-ANTIBODIES AND TNF RECEPTOR IMMUNOGLOBULIN FUSION PROTEINS [J].
BAKER, D ;
BUTLER, D ;
SCALLON, BJ ;
ONEILL, JK ;
TURK, JL ;
FELDMANN, M .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1994, 24 (09) :2040-2048
[5]   PRODUCTION OF TUMOR NECROSIS FACTOR BY RAT MESANGIAL CELLS IN RESPONSE TO BACTERIAL LIPOPOLYSACCHARIDE [J].
BAUD, L ;
OUDINET, JP ;
BENS, M ;
NOE, L ;
PERALDI, MN ;
RONDEAU, E ;
ETIENNE, J ;
ARDAILLOU, R .
KIDNEY INTERNATIONAL, 1989, 35 (05) :1111-1118
[6]  
BEMELMANS MHA, 1993, J IMMUNOL, V151, P5554
[7]   EVIDENCE FOR DIFFERENT INTERLEUKIN-1 RECEPTORS IN MURINE B-CELL AND T-CELL LINES [J].
BOMSZTYK, K ;
SIMS, JE ;
STANTON, TH ;
SLACK, J ;
MCMAHAN, CJ ;
VALENTINE, MA ;
DOWER, SK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (20) :8034-8038
[8]   PURIFICATION, CLONING, EXPRESSION AND BIOLOGICAL CHARACTERIZATION OF AN INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN [J].
CARTER, DB ;
DEIBEL, MR ;
DUNN, CJ ;
TOMICH, CSC ;
LABORDE, AL ;
SLIGHTOM, JL ;
BERGER, AE ;
BIENKOWSKI, MJ ;
SUN, FF ;
MCEWAN, RN ;
HARRIS, PKW ;
YEM, AW ;
WASZAK, GA ;
CHOSAY, JG ;
SIEU, LC ;
HARDEE, MM ;
ZURCHERNEELY, HA ;
REARDON, IM ;
HEINRIKSON, RL ;
TRUESDELL, SE ;
SHELLY, JA ;
EESSALU, TE ;
TAYLOR, BM ;
TRACEY, DE .
NATURE, 1990, 344 (6267) :633-638
[9]   INTERLEUKIN-1 TYPE-II RECEPTOR - A DECOY TARGET FOR IL-1 THAT IS REGULATED BY IL-4 [J].
COLOTTA, F ;
RE, F ;
MUZIO, M ;
BERTINI, R ;
POLENTARUTTI, N ;
SIRONI, M ;
GIRI, JG ;
DOWER, SK ;
SIMS, JE ;
MANTOVANI, A .
SCIENCE, 1993, 261 (5120) :472-475
[10]   EXPRESSION OF HUMAN ALPHA-TUBULIN GENES - INTERSPECIES CONSERVATION OF 3' UNTRANSLATED REGIONS [J].
COWAN, NJ ;
DOBNER, PR ;
FUCHS, EV ;
CLEVELAND, DW .
MOLECULAR AND CELLULAR BIOLOGY, 1983, 3 (10) :1738-1745