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 expos ure (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 condi tions, This delay was abolished upon addition of betaine, which acts a s an osmolyte in Kupffer cells, When LPS was added to Kupffer cells th at had been preexposed to hyperosmotic medium for 24 h, the LPS-induce d TNF-alpha release was inhibited by 90% when compared to normoosmotic conditions, Likewise, the LPS-induced increase in TNF-alpha mRNA leve ls was largely abolished, Inhibition of TNF-alpha release and of the i ncrease in the TNF-alpha mRNA level in response to hyperosmolarity/LPS , however, was largely overcome when indomethacin or betaine was prese nt during the hyperosmotic preincubation period, Because betaine has r ecently been shown to inhibit the hyperosmolarity-induced induction of cyclooxygenase-2 and stimulation of prostaglandin production, these f indings suggest that the effect of betaine in restoring the LPS-induce d TNF-alpha response in hyperosmotically exposed Kupffer cells is medi ated by an inhibition of prostaglandin synthesis, The findings point t o a regulatory role of cell volume and betaine for TNF-alpha productio n by liver macrophages, suggesting a new role of osmolytes in modulati ng immune function.