Bovine glycomacropeptide induces cytokine production in human monocytes through the stimulation of the MAPK and the NF-κB signal transduction pathways

Background and purpose: Bovine glycomacropeptide (BGMP) is a natural milk peptide that is produced naturally in the gastrointestinal tract during digestion. Glycomacropepide has intestinal anti-inflammatory activity, but the mechanism of action is unknown. Here we have characterized the effects of BGMP on monocytes. Experimental approach: We have used human THP-1 cells as an in vitro monocyte model. The effect of BGMP on the secretion of tumour necrosis factor (TNF), interleukin (IL)-1 beta and IL-8 was assessed, as well as the involvement of the NF-kappa B and MAP kinase signalling pathways. The stimulatory effect of BGMP was also tested in human peripheral blood monocytes. Key results: BGMP up-regulated the secretion of TNF, IL-1 beta and IL-8 in a concentration-dependent fashion. The biological activity was exerted by the intact peptide, because cytokine secretion was not affected by protease inhibitors. The secretion of IL-8 and specially TNF and IL-1 beta was blocked by PD98059, SP600125, SB203580 and Bay11-7082, suggesting the involvement of the MAP kinases p38, c-Jun N-terminal kinase and ERK and particularly the NF-kappa B pathway, although IL-8 secretion was independent of p38. BGMP was shown to elicit the phosphorylation of I kappa B-alpha and the nuclear translocation of the NF-kappa B subunits p50 and p65. The effect of BGMP on cytokine secretion was validated in human primary blood monocytes. Conclusions and implications: BGMP stimulates human monocytes, operating via MAP kinase and NF-kappa B pathways. BGMP may exert an indirect intestinal anti-inflammatory effect by potentiating host defences against invading microorganisms.