Albumin induces interleukin-6 release from primary human proximal tubule epithelial cells.
BACKGROUND
Proximal tubule epithelial cells (PTECs) release proinflammatory and profibrogenic mediators when exposed to serum albumin that may contribute to progression of kidney disease. Interleukin 6 (IL-6) may influence renal fibrosis by modulating transforming growth factor beta1 (TGFbeta1) signalling. PTECs have been demonstrated to produce IL-6 in response to albumin treatment, but the mechanism has not been investigated. We hypothesized that albumin would induce release of IL-6 from PTECs, which would be sensitive to inhibition of PI3K, ERK1,2, p38 MAPK and NFkB.


METHODS
Primary human PTECs were exposed to albumin (0.75-150 micronM) for 8 and 24 hours. IL-6 release was determined using enzyme-linked immunosorbent assay (ELISA). The effects of LY294002 (10 micronM), NH4Cl (10 mM), pyrrolidine dithiocarbamate (PDTC) (20 micronM), CAPE (17.5 micronM), PD098059 (20 micronM), SB202190 (5 micronM) and MG132 (10 micronM) on albumin-mediated IL-6 release were studied.


RESULTS
Albumin caused a significant time- and concentration-dependent increase in IL-6 release by PTECs. LY294002, NH4Cl, CAPE, PD098059 and SB202190 all reduced albumin-mediated IL-6 release, but neither PDTC nor MG132 had any effect.


CONCLUSIONS
These data demonstrate that albumin induces IL-6 release by primary human PTECs, and support a role for endocytosis, p38 MAPK, ERK1,2 and in this process.
Pearson
Alex L
AL
South West Thames Institute for Renal Research, St. Helier Hospital, Carshalton, Surrey - UK. alexpearson115@tiscali.co.uk
Colville-Nash
Paul
P
Kwan
Jonathan T C
JT
Dockrell
Mark E C
ME
D000975:Antioxidants / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline / Q000031:analogs & derivatives; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D012709:Serum Albumin / Q000494:pharmacology*; D013859:Thiocarbamates; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000097782:NF-kappaB-Inducing Kinase
D000975:Antioxidants; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D015850:Interleukin-6; D019950:Mitogen-Activated Protein Kinase 1; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D012709:Serum Albumin; D013859:Thiocarbamates; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C066229:prolinedithiocarbamate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one