l-Proline-based-cyclic dipeptides from Pseudomonas sp. (ABS-36) inhibit pro-inflammatory cytokines and alleviate crystal-induced renal injury in mice

Int Immunopharmacol. 2019 Aug;73:395-404. doi: 10.1016/j.intimp.2019.05.044. Epub 2019 May 28.

Abstract

Study on the constituents of bioactive culture broth extract (CBE) of Pseudomonas sp. (ABS-36) explored the secretion of an array of cyclic dipeptides (CDPs) and twenty of them had been isolated and reported in the present paper. Six major CDPs [(cyclo(Leu-Pro) (1), cyclo(Val-Pro) (2), cyclo(Leu-hydroxy-Pro) (9), cyclo(Pro-Tyr) (10), cyclo(Pro-Ala) (11) and cyclo(Gly-Pro) (12)] exhibited pan cytokine inhibition effect by inhibiting key pro-inflammatory cytokines IL-1β, TNF-α and IL-6 tested under various cell based assays. With this background, the effect of these six CDPs in treating renal inflammation was screened using crystal-induced nephropathy model in mice at 50 mg/kg body weight through oral administration. cis-Cyclo(Val-Pro) (2) exhibited 57% inhibition of plasma IL-1β protein expression and 35.2% inhibition of elevated blood urea nitrogen. Further, cis-cyclo(Val-Pro) (2) attenuated renal injury as demonstrated by significant reduction of mRNA expressions of IL-1β (P < 0.01) and kidney injury marker-1 (P < 0.001). Furthermore, evaluation of tubular-necrosis, -dilation and -cast in the histological sections exhibited moderate protection of renal tissues by cis-cyclo(Val-Pro) (2). All the tested CDPs reduced the nitrite production and were interestingly non-cytotoxic.

Keywords: Cyclic dipeptides; Cyclo(Val-Pro); IL-1β; IL-6; Oxalate-induced nephropathy; Pseudomonas; Renal inflammation; TNF-α.

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / pathology
  • Animals
  • Cell Survival / drug effects
  • Cytokines / metabolism
  • Dipeptides / therapeutic use*
  • Kidney / drug effects
  • Kidney / pathology
  • Mice
  • Mice, Inbred C57BL
  • Oxalic Acid
  • Peptides, Cyclic / therapeutic use*
  • Proline*
  • Pseudomonas*
  • RAW 264.7 Cells

Substances

  • Cytokines
  • Dipeptides
  • Peptides, Cyclic
  • Proline
  • Oxalic Acid