title: Synergy between glycated human serum albumin and tumor necrosis factor-alpha for interleukin-8 gene expression and protein secretion in human retinal pigment epithelial cells.
abstract: Chemokine production by human retinal pigment epithelium (HRPE) cells is believed to play an important role in ocular inflammation and immune responses. In our previous studies, we demonstrated that glycated human serum albumin (GHSA) strongly stimulates HRPE cells and human corneal keratocytes to produce chemokines. In the present study, we further examined the effects of GHSA on TNF-alpha- and IL-1 beta-induced HRPE IL-8 and monocyte chemoattractant protein (MCP)-1 gene expression and protein secretion in HRPE. At maximally effective concentrations, GHSA (2000 micrograms/ml) potentiated TNF-alpha (20 ng/ml)-stimulated HRPE IL-8 secretion approximately 7-fold. Consistent with the above observations were the time- and dose-dependent increases in the steady-state IL-8 mRNA after coadministration with these two factors, although the half-life of IL-8 mRNA (30 minutes) was not altered by GHSA. In contrast to IL-8, the TNF-alpha-induced HRPE MCP-1 gene expression was only slightly enhanced by GHSA. Moreover, potentiation of HRPE IL-8 generation by GHSA appeared to be selective for TNF-alpha because, under similar conditions, GHSA was unable to enhance the IL-1 beta-stimulated IL-8 gene expression and protein secretion. The IL-1 beta-stimulated HRPE MCP-1 production was also unchanged by GHSA. Collectively, these results suggest specific potentiation of TNF-alpha-induced HRPE IL-8 by human serum albumin that has been glycated either during circulation or locally within tissue. This interaction may be relevant to a variety of ocular diseases involving breakdown of the blood-retinal barrier.
authors.affiliation: Department of Ophthalmology, University of Michigan, Ann Arbor 48105, USA.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Bian
authors.forename: S G
authors.initials: SG
authors.lastname: Elner
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: V M
authors.initials: VM
authors.lastname: Elner
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D017127:Glycation End Products, Advanced; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism*; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000093423:Glycated Serum Albumin
chemical_list: D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D016209:Interleukin-8; D012333:RNA, Messenger; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; D000093423:Glycated Serum Albumin