Porphyrins as new endogenous anti-inflammatory agents.
A series of porphyrins, tetrapyrrole natural organic compounds, are evaluated here as endogenous anti-inflammatory agents. They directly inhibit the activity of Fyn, a non-receptor Src-family tyrosine kinase, triggering anti-inflammatory events associated with down-regulation of T-cell receptor signal transduction, leading to inhibition of tumor necrosis factor alpha (TNF-α) production. This is one of the major pro-inflammatory cytokines, associated with diseases such as diabetes, tumorigenesis, rheumatoid arthritis, and inflammatory bowel disease. Porphyrins, as a chemical class, inhibited Fyn kinase activity in a non-competitive, linear-mixed fashion. In cell-based in vitro experiments on polymorphonuclear cells, porphyrins inhibited TNF-α cytokine production, T-cell proliferation, and the generation of free radicals in the oxidative burst, in a concentration-related manner. In vivo, lipopolysaccharide-induced TNF-α production in mice was inhibited by several of the porphyrins. These findings may be very important for the overall understanding of the role(s) of porphyrins in inflammation and their possible application as new anti-inflammatory agents.
GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. dubravko.jelic@glpg.com
Dubravko
D
Jelić
Iva
I
Tatić
Marija
M
Trzun
Boška
B
Hrvačić
Karmen
K
Brajša
Donatella
D
Verbanac
Marija
M
Tomašković
Ognjen
O
Čulić
Roberto
R
Antolović
Ines
I
Glojnarić
Ivana
I
Weygand-Đurašević
Sanda
S
Vladimir-Knežević
Boris
B
Mildner
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011166:Porphyrins / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D061987:Sf9 Cells; D018411:Spodoptera; D013936:Thymidine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D011166:Porphyrins; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051076:Proto-Oncogene Proteins c-fyn; D013936:Thymidine