title: The intestinal antiinflammatory agent glycomacropeptide has immunomodulatory actions on rat splenocytes.
abstract: Bovine glycomacropeptide (GMP) is an immunologically active milk peptide that is a part of the normal human diet. GMP has therapeutic value in preclinical models of intestinal inflammation, and its mechanism may be related to effects on lymphocytes. This study focuses on the actions of GMP on rat splenocytes in vitro and in vivo. Bovine serum albumin and lactoferrin were used for comparative purposes. GMP (0.01-0.1mgmL(-1)) enhanced Concanavalin A (ConA) evoked but not basal splenocyte proliferation. At 1mgmL(-1) GMP lost this effect but augmented basal TNF-alpha secretion and also iNOS and COX2 expression. IFN-gamma, IL-2 and IL-17 were not affected by GMP in quiescent splenocytes, but IL-10 was augmented at all concentrations tested. On the other hand, GMP produced a marked inhibitory effect (70%) on IFN-gamma secretion and to a lower extent (50%) also on TNF-alpha. GMP was shown to block STAT4 but not IkappaB-alpha phosphorylation. The Treg marker Foxp3 was markedly upregulated by GMP. Bovine serum albumin had some effects on splenocyte function which were of lower magnitude and not entirely coincidental, while lactoferrin had a strong antiproliferative effect, as expected, indicating a specific effect of GMP. When administered for 3 days to normal Wistar rats, GMP reproduced the Foxp3 induction effect observed previously in vitro. This was observed in splenocytes but not in thymocytes, and only when administered by the oral rather than the intraperitoneal route. Thus our results support the hypothesis that GMP may limit intestinal inflammation acting at least in part on lymphocytes.
authors.affiliation: Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Requena
authors.forename: Raquel
authors.initials: R
authors.lastname: González
authors.forename: Rocío
authors.initials: R
authors.lastname: López-Posadas
authors.forename: Ana
authors.initials: A
authors.lastname: Abadía-Molina
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Suárez
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.forename: Fermín Sánchez
authors.initials: FS
authors.lastname: de Medina
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Augustin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002364:Caseins / Q000494:pharmacology*; D049109:Cell Proliferation; D003208:Concanavalin A; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008565:Membrane Proteins; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010750:Phosphoproteins; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D050797:STAT4 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002364:Caseins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D050797:STAT4 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C065989:caseinomacropeptide; C083557:p112 protein, rat; D003208:Concanavalin A; D016753:Interleukin-10; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat