PMID- 12427122
OWN - NLM
STAT- MEDLINE
DCOM- 20030523
LR  - 20061115
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 62
IP  - 6
DP  - 2002 Dec
TI  - Endocytosis of light chains induces cytokines through activation of NF-kappaB in 
      human proximal tubule cells.
PG  - 1977-88
AB  - BACKGROUND: In proteinuric states increased cytokine production through 
      endocytosis of filtered proteins by proximal tubule cells (PTCs) has been 
      proposed as a major mechanism mediating tubulointerstitial injury and progressive 
      kidney disease. We studied the effects of six different light chains (LCs) on the 
      production of cytokines in cultured human PTCs. METHODS: LCs were isolated and 
      purified from the urine of patients with myeloma and human PTCs were exposed to 
      either LC or human serum albumin (HSA) for up to 24 hours. LC endocytosis was 
      monitored by immunocytochemistry. Cytokines were determined by enzyme-linked 
      immunosorbent assay (ELISA) in the supernatants and activation of nuclear 
      factor-kappa B (NF-kappaB) was detected by electrophoretic mobility shift assays 
      (EMSA) and immunocytochemistry. RESULTS: Endocytosis of LCs induced the release 
      of interleukins (IL) IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1); 
      however, there was considerable variability among the six different LCs. In 
      contrast, HSA had no effect on cytokine production even at very high 
      concentrations. Removal of LC-containing media resulted in cessation of IL-6 
      release. LC-induced cytokine release was associated with nuclear translocation of 
      NF-kappaB subunits p50 and p65, as demonstrated by both EMSA and 
      immunocytochemistry. Inhibitors of NF-kappaB, aspirin and 
      pyrrolidineditiocarbamate (PDTC) markedly suppressed LC-induced cytokine 
      production. CONCLUSION: LC endocytosis leads to production of inflammatory 
      cytokines through activation of NF-kappaB. This may be an important mechanism of 
      chronic tubulointerstitial inflammation process commonly seen in multiple 
      myeloma. These findings also point out a potential role by filterable 
      low-molecular-weight proteins, like LCs, in PTC injury during all proteinuric 
      diseases.
FAU - Sengul, Sule
AU  - Sengul S
AD  - Department of Medicine, Section of Nephrology, Tulane Medical Center, Tulane 
      Cancer Center, and Veterans Administration Medical Center, New Orleans, 
      Louisiana, USA.
FAU - Zwizinski, Craig
AU  - Zwizinski C
FAU - Simon, Eric E
AU  - Simon EE
FAU - Kapasi, Aditi
AU  - Kapasi A
FAU - Singhal, Pravin C
AU  - Singhal PC
FAU - Batuman, Vecihi
AU  - Batuman V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Chemokine CCL2)
RN  - 0 (Immunoglobulin Light Chains)
RN  - 0 (Interleukin-6)
RN  - 0 (Interleukin-8)
RN  - 0 (NF-kappa B)
RN  - 0 (Serum Albumin)
SB  - IM
MH  - Cells, Cultured
MH  - Chemokine CCL2/biosynthesis/metabolism
MH  - Electrophoretic Mobility Shift Assay
MH  - *Endocytosis
MH  - Fluorescent Antibody Technique, Indirect
MH  - Humans
MH  - Immunoglobulin Light Chains/metabolism/*pharmacology
MH  - Interleukin-6/biosynthesis/metabolism
MH  - Interleukin-8/biosynthesis/metabolism
MH  - Kidney Tubules, Proximal/*cytology/*metabolism
MH  - Multiple Myeloma/metabolism
MH  - NF-kappa B/antagonists & inhibitors/*metabolism
MH  - Serum Albumin/pharmacology
EDAT- 2002/11/13 04:00
MHDA- 2003/05/24 05:00
CRDT- 2002/11/13 04:00
PHST- 2002/11/13 04:00 [pubmed]
PHST- 2003/05/24 05:00 [medline]
PHST- 2002/11/13 04:00 [entrez]
AID - S0085-2538(15)48765-4 [pii]
AID - 10.1046/j.1523-1755.2002.00660.x [doi]
PST - ppublish
SO  - Kidney Int. 2002 Dec;62(6):1977-88. doi: 10.1046/j.1523-1755.2002.00660.x.