Immunomodulatory peptide from cystatin, a natural cysteine protease inhibitor, against leishmaniasis as a model macrophage disease.
Cystatin, a natural cysteine protease inhibitor, has strong antileishmanial activity, which is due to its potential to induce nitric oxide (NO) generation from macrophages. Cysteine protease-inhibitory activity and NO-up-regulatory activity correspond to different regions, as revealed by the dissection of cystatin cDNA into nonoverlapping fragments. By using synthetic overlapping peptides, the NO-up-regulatory activity was found to be confined to a 10-mer sequence. In addition to having reasonable inhibitory effects on amastigote multiplication within macrophages (50% inhibitory concentration, 5.2 microg/ml), 97 and 93% suppression, respectively, of liver and spleen parasite burdens was achieved with the 10-mer peptide at a dose of 0.5 mg/kg of body weight/day, given consecutively for 4 days along with a suboptimal dose of gamma interferon in a 45-day mouse model of visceral leishmaniasis. Peptide treatment modulated the levels of cytokine secretion by infected splenocytes, with increased levels of interleukin-12 and tumor necrosis factor alpha and increased inducible NO synthase production, and also resulted in resistance to reinfection. The generation of a natural peptide from cystatin with robust immunomodulatory potential may therefore provide a promising therapeutic agent for macrophage-associated diseases.
Mukherjee
Snigdha
S
Molecular Cell Biology Laboratory, Indian Institute of Chemical Biology, Calcutta, India.
Ukil
Anindita
A
Das
Pijush K
PK
D000595:Amino Acid Sequence; D000818:Animals; D015891:Cystatins / Q000627:therapeutic use*; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000096:biosynthesis; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology; D008264:Macrophages / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis; D010446:Peptide Fragments / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide