Modulation of cytokine production by some phthalimido-desmuramyl dipeptides and their cytotoxicity.
Muramyl dipeptide (MDP) is the smallest bacterial cell wall peptidoglycan component having immunomodulatory activity. In an attempt to obtain MDP derivatives with improved and better defined pharmacological profiles we synthesized a new lipophilic phthalimido-desmuramyl dipeptide, LK 508. This novel MDP analogue and three structurally related phthalimido-desmuramyl dipeptides (LK 413, LK 511 and LK 512) were evaluated immunologically. Their ability to modulate the production of cytokines was measured in vitro by their inclusion in cultures of human peripheral blood mononuclear cells (PBMC) activated by ionomycin and phorbol-12-myristate-13-acetate (PMA). The results were compared with the analogous activity of MDP. All compounds tested are strong up-regulators of IL-12 synthesis. All compounds except LK 512 also stimulated IFNgamma synthesis. LK 508, LK 511 and LK 512 are effective in up-regulating IL-2 production. LK 508 and LK 512 considerably up-regulate the synthesis of IL-4 and IL-10. LK 413 and MDP stimulated the production of Th1 promoting and Th1 (IFNgamma and IL-12) cytokines, while LK 508, LK 511 and LK 512 non-selectively up-regulated the production of both Th1 and Th2-types of (IL-4 and IL-10) cytokines. None of the phthalimido-desmuramyl dipeptides was cytotoxic in vitro against the normal cell line HUVEC (human endothelial cells) thereby indicating their potential for use in vivo.
Gobec
Stanislav
S
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia. gobecs@ffa.uni-lj.si
Sollner-Dolenc
Marija
M
Urleb
Uros
U
Wraber
Branka
B
Simcic
Sasa
S
Filipic
Metka
M
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000138:chemical synthesis / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008956:Models, Chemical; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D018418:Th2 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007378:Interleukins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D015759:Ionomycin