PMID- 12164866
OWN - NLM
STAT- MEDLINE
DCOM- 20030211
LR  - 20161124
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 62
IP  - 3
DP  - 2002 Sep
TI  - Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via 
      NF-kappaB dependent up-regulation of IL-8 and MCP-1.
PG  - 846-56
AB  - BACKGROUND: Shiga toxin (Stx)-producing E. coli is a causative agent of the 
      epidemic form of hemolytic uremic syndrome (HUS), the most common cause of acute 
      renal failure in children. Endothelial injury and leukocyte activation are 
      instrumental to the development of microangiopathic lesions. To obtain more 
      insight into the mechanisms favoring endothelium-leukocyte interaction, we 
      studied (1) the effect of Stx-2 on leukocyte adhesion and transmigration in human 
      endothelial cells under flow; (2) the effect of Stx-2 on endothelial expression 
      of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and their 
      functional role in the adhesive phenomena; and (3) the role of nuclear 
      factor-kappaB (NF-kappaB) in endothelial chemokine expression. METHODS: For 
      adhesion experiments, human umbilical vein endothelial cells (HUVEC) and human 
      glomerular endothelial cells (GEC) were incubated for 24 hours with Stx-2 (25 
      pmol/L), with or without anti-IL-8 or MCP-1 antibodies, and then exposed to 
      leukocyte suspension under flow (1.5 dynes/cm2). IL-8 and MCP-1 expression was 
      evaluated in Stx-2 treated endothelial cells (6 hours) by Northern blot. 
      NF-kappaB activity was assessed by electrophoretic mobility shift assay. The role 
      of NF-kappaB in Stx-induced chemokines was evaluated by transfecting HUVEC with 
      an adenovirus coding for IkappaBalpha. RESULTS: Stx-2 significantly enhanced the 
      number of leukocytes that adhered and then migrated across the endothelium. Stx-2 
      increased the expression of IL-8 and MCP-1, which was preceded by NF-kappaB 
      activation. Blocking of endothelial IL-8 and MCP-1 with corresponding antibodies 
      significantly inhibited Stx-induced leukocyte adhesion and migration either in 
      HUVEC or GEC. Adenovirus-mediated gene transfer of IkappaBalpha down-regulated 
      IL-8 and MCP-1 mRNA and also inhibited the adhesion and transmigration of 
      leukocytes in Stx-treated HUVEC. CONCLUSIONS: Stx-2 via a transcriptional 
      activation mechanism specifically mediated by NF-kappaB up-regulates endothelial 
      MCP-1 and IL-8. Both chemokines are important modulators of leukocyte adhesion 
      and transmigration under flow. These findings might be relevant to understand the 
      nature of microvascular lesions in HUS and open future perspectives for better 
      treatment of microvascular thrombosis.
FAU - Zoja, Carla
AU  - Zoja C
AD  - Mario Negri Institute for Pharmacological Research, Azienda Ospedaliera, Ospedali 
      Riuniti di Bergamo, Via Gavazzeni 11, 24125 Bergamo, Italy. zoja@marionegri.it
FAU - Angioletti, Stefania
AU  - Angioletti S
FAU - Donadelli, Roberta
AU  - Donadelli R
FAU - Zanchi, Cristina
AU  - Zanchi C
FAU - Tomasoni, Susanna
AU  - Tomasoni S
FAU - Binda, Elena
AU  - Binda E
FAU - Imberti, Barbara
AU  - Imberti B
FAU - te Loo, Maroeska
AU  - te Loo M
FAU - Monnens, Leo
AU  - Monnens L
FAU - Remuzzi, Giuseppe
AU  - Remuzzi G
FAU - Morigi, Marina
AU  - Morigi M
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Chemokine CCL2)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Interleukin-8)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Shiga Toxin 2)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
SB  - IM
CIN - Kidney Int. 2002 Sep;62(3):1088-90. PMID: 12164895
MH  - Adenoviridae/genetics
MH  - Cell Adhesion/drug effects/immunology
MH  - Cell Movement/drug effects/immunology
MH  - Cells, Cultured
MH  - Chemokine CCL2/*genetics
MH  - Endothelium, Vascular/cytology/immunology
MH  - Gene Expression/drug effects/immunology
MH  - Hemolytic-Uremic Syndrome/immunology
MH  - Humans
MH  - I-kappa B Proteins/genetics
MH  - Interleukin-8/*genetics
MH  - Kidney Glomerulus/cytology/*immunology
MH  - Leukocytes/*cytology
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/*metabolism
MH  - RNA, Messenger/analysis
MH  - Shiga Toxin 2/*toxicity
MH  - Transfection
MH  - Umbilical Veins/cytology
MH  - Up-Regulation/drug effects/immunology
EDAT- 2002/08/08 10:00
MHDA- 2003/02/13 04:00
CRDT- 2002/08/08 10:00
PHST- 2002/08/08 10:00 [pubmed]
PHST- 2003/02/13 04:00 [medline]
PHST- 2002/08/08 10:00 [entrez]
AID - S0085-2538(15)48619-3 [pii]
AID - 10.1046/j.1523-1755.2002.00503.x [doi]
PST - ppublish
SO  - Kidney Int. 2002 Sep;62(3):846-56. doi: 10.1046/j.1523-1755.2002.00503.x.