Modulation of tumour necrosis factor production with desmuramyldipeptide analogues.
Some synthetic analogues of the immunomodulatory agent muramyl dipeptide (MDP), i.e. phthalimido- (LK-511, LK-413, LK-512, LK-423, LK-508), adamantyl- (LK-415, LK-517), 7-oxoalkyl-(LK-409) desmuramylpeptides were assessed for the tumour necrosis factor (TNF) inducing activity and the ability to modulate TNF production in in vitro phorbol 12-myristate 13-acetate (PMA) & ionomycin stimulated cultures of human peripheral blood mononuclear cells. A kinetic study over a 40-hour period indicated that desmuramyldipeptides were weak TNF inducers compared to romurtide, PMA & ionomycin or lipopolysaccharide. By contrast, they showed the potential to up- or down-regulate the production of TNF evoked by PMA & ionomycin, which was strongly dependent on the time of the stimulation. After 4h of stimulation, the TNF secretion was augmented by LK-508, LK-409 and LK-511, after 18 h by LK-409 and LK-423, and after 40 h by LK-423, LK-511, LK-415 and LK-512. However, LK-517 and LK-512 inhibited the secretion of TNF after the 18-h period.
Simcic
S
S
Institute of Microbiology and Immunology, Medical Faculty, University of Ljubljana, Slovenia.
Wraber
B
B
Sollner
M
M
Urleb
U
U
Gobec
S
S
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D004338:Drug Combinations; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000276:Adjuvants, Immunologic; D004338:Drug Combinations; D007476:Ionophores; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate