Modulation of tumor necrosis factor-alpha release by anisoosmolarity and betaine in rat liver macrophages (Kupffer cells).
Hypoosmotic exposure (205 mosmol/l) of rat liver macrophages together with lipopolysaccharide (LPS) inhibited the LPS-induced tumor necrosis factor-alpha (TNF-alpha) release by about 60% and markedly diminished the LPS-induced increase of TNF-alpha mRNA levels. Hyperosmotic exposure (405 mosmol/l) had no effect on total TNF-alpha release, however, both TNF-alpha accumulation in the medium and the LPS-induced increase of TNF-alpha mRNA levels were significantly delayed under these conditions. This delay was abolished upon addition of betaine, which acts as an osmolyte in Kupffer cells. When LPS was added to Kupffer cells that had been preexposed to hyperosmotic medium for 24 h, the LPS-induced TNF-alpha release was inhibited by 90% when compared to normoosmotic conditions. Likewise, the LPS-induced increase in TNF-alpha mRNA levels was largely abolished. Inhibition of TNF-alpha release and of the increase in the TNF-alpha mRNA level in response to hyperosmolarity/LPS, however, was largely overcome when indomethacin or betaine was present during the hyperosmotic preincubation period. Because betaine has recently been shown to inhibit the hyperosmolarity-induced induction of cyclooxygenase-2 and stimulation of prostaglandin production, these findings suggest that the effect of betaine in restoring the LPS-induced TNF-alpha response in hyperosmotically exposed Kupffer cells is mediated by an inhibition of prostaglandin synthesis. The findings point to a regulatory role of cell volume and betaine for TNF-alpha production by liver macrophages, suggesting a new role of osmolytes in modulating immune function.
Zhang
F
F
Medizinische Universitätsklinik, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich Heine University, Düsseldorf, Germany.
Warskulat
U
U
Häussinger
D
D
D000818:Animals; D001622:Betaine / Q000494:pharmacology*; D015152:Blotting, Northern; D004797:Enzyme-Linked Immunosorbent Assay; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007213:Indomethacin / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009994:Osmolar Concentration; D051381:Rats; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D001622:Betaine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007213:Indomethacin