PMID- 16452499
OWN - NLM
STAT- MEDLINE
DCOM- 20060727
LR  - 20111102
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 17
IP  - 3
DP  - 2006 Mar
TI  - CD40L proinflammatory and profibrotic effects on proximal tubular epithelial 
      cells: role of NF-kappaB and lyn.
PG  - 627-36
AB  - Chronic allograft nephropathy (CAN) is the main cause of renal graft loss, but 
      its pathogenic mechanisms are still unclear. Immune system activation has been 
      suggested as a key event in the development of CAN. CD40 is a co-stimulatory 
      protein whose expression is upregulated in proximal tubular epithelial cells 
      (PTEC) in acute rejection. This receptor interacts with CD40L, expressed by 
      activated T cells. CD40L induces the production by PTEC of different 
      proinflammatory cytokines, but very little is known of its profibrotic effects. 
      The aim of this study was to investigate the effect of CD40/CD40L interaction on 
      PTEC expression of plasminogen activator inhibitor-1 (PAI-1), a powerful 
      profibrotic mediator, and monocyte chemoattractant protein-1 (MCP-1), a 
      proinflammatory cytokine, and to investigate the signaling pathways that lead to 
      these effects. Soluble CD40L induced a time-dependent increase in both PAI-1 and 
      MCP-1 gene expression and protein production in PTEC. CD40 cross-linking on PTEC 
      caused TNF-R-associated factors 2 and 6 membrane translocation. This event led to 
      NF-kappaB activation, through the NF-kappaB-inducing kinase, and to a significant 
      increase in the phosphorylation of lyn, a src-related tyrosine kinase. Lyn, upon 
      phosphorylation, became strictly associated with caveolin-1, a scaffolding 
      protein enriched in caveolae. Lyn inhibition did not have any effect on 
      CD40L-induced NF-kappaB activation and MCP-1 expression but abolished PAI-1 
      induction. On the contrary, NF-kappaB inhibition significantly reduced only MCP-1 
      expression. In conclusion, CD40L could play a key role in the pathogenesis of CAN 
      through PAI-1 induction. CD40L profibrotic and proinflammatory effects are 
      mediated by different signaling pathways, suggesting that drugs that inhibit 
      inflammation may not be equally effective in reducing fibrosis.
FAU - Pontrelli, Paola
AU  - Pontrelli P
AD  - Clinical Pathology, Department of Biomedical Sciences, University of Foggia, 
      Italy.
FAU - Ursi, Michele
AU  - Ursi M
FAU - Ranieri, Elena
AU  - Ranieri E
FAU - Capobianco, Carmen
AU  - Capobianco C
FAU - Schena, Francesco P
AU  - Schena FP
FAU - Gesualdo, Loreto
AU  - Gesualdo L
FAU - Grandaliano, Giuseppe
AU  - Grandaliano G
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060201
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (NF-kappa B)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 147205-72-9 (CD40 Ligand)
RN  - EC 2.7.10.2 (lyn protein-tyrosine kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Analysis of Variance
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - CD40 Ligand/drug effects/*metabolism
MH  - Cells, Cultured
MH  - Humans
MH  - Immunoprecipitation
MH  - Kidney Tubules, Proximal/drug effects/*metabolism
MH  - Microscopy, Confocal
MH  - NF-kappa B/*metabolism
MH  - Plasminogen Activator Inhibitor 1/*pharmacology
MH  - Probability
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sensitivity and Specificity
MH  - Signal Transduction
MH  - src-Family Kinases/*metabolism
EDAT- 2006/02/03 09:00
MHDA- 2006/07/28 09:00
CRDT- 2006/02/03 09:00
PHST- 2006/02/03 09:00 [pubmed]
PHST- 2006/07/28 09:00 [medline]
PHST- 2006/02/03 09:00 [entrez]
AID - ASN.2005020202 [pii]
AID - 10.1681/ASN.2005020202 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2006 Mar;17(3):627-36. doi: 10.1681/ASN.2005020202. Epub 2006 
      Feb 1.