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


METHODS
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)-1beta and IL-8 was assessed, as well as the involvement of the NF-kappaB and MAP kinase signalling pathways. The stimulatory effect of BGMP was also tested in human peripheral blood monocytes.


RESULTS
BGMP up-regulated the secretion of TNF, IL-1beta 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-1beta 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-kappaB pathway, although IL-8 secretion was independent of p38. BGMP was shown to elicit the phosphorylation of IkappaB-alpha and the nuclear translocation of the NF-kappaB subunits p50 and p65. The effect of BGMP on cytokine secretion was validated in human primary blood monocytes.


CONCLUSIONS
BGMP stimulates human monocytes, operating via MAP kinase and NF-kappaB pathways. BGMP may exert an indirect intestinal anti-inflammatory effect by potentiating host defences against invading microorganisms.
Requena
Pilar
P
Department of Biochemistry, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Granada, Granada, Spain.
Daddaoua
Abdelali
A
Guadix
Emilia
E
Zarzuelo
Antonio
A
Suárez
María Dolores
MD
Sánchez de Medina
Fermín
F
Martínez-Augustin
Olga
O
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002364:Caseins / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002364:Caseins; D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D010446:Peptide Fragments; D051996:Transcription Factor RelA; C065989:caseinomacropeptide; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases