Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis.
Steroidal anti-inflammatory drugs induce proteins that inhibit phospholipase A(2) (PLA(2)), including uteroglobin and lipocortin-1 (annexin I). Uteroglobin and lipocortin-1 retain several conserved sequences. Based on these sequences, several nonapeptides (antiflammins) were synthesized. These nonapeptides were shown to have anti-inflammatory effects in vitro and in vivo, possibly by inhibiting PLA(2). Subsequent research showed that PLA(2) is activated by transglutaminase 2 (TGase 2). We hypothesize here that TGase 2 inhibitors may increase the anti-inflammatory efficacy of inhibiting PLA(2) activity. To test this theory, we constructed recombinant peptides containing sequences from pro-elafin (for inhibition of TGase 2), and from lipocortin-1, lipocortin-5, and uteroglobin (for inhibition of PLA(2)). The recombinant peptides, which had dual inhibitory effects on purified TGase 2 and PLA(2), reversed the inflammation of allergic conjunctivitis to ragweed in a guinea pig model. The present work suggests that novel recombinant peptides may be safe and effective agents for the treatment of various inflammatory diseases.
Sohn
Joonhong
J
Department of Ophthalmology, Asan Medical Center, Seoul, Republic of Korea.
Kim
Tae-Im
TI
Yoon
Young-Hee
YH
Kim
Joo-Yong
JY
Kim
Soo-Youl
SY
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003233:Conjunctivitis, Allergic / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D007249:Inflammation; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D011994:Recombinant Proteins; D011503:Transglutaminases