A diketopiperazine fragment of human serum albumin modulates T-lymphocyte cytokine production through rap1.
BACKGROUND
Aspartyl-alanyl- diketopiperazine (DA-DKP) is generated by cleavage and cyclization from the N-terminus of human albumin during the preparation of commercial serum albumin product. Antigen-stimulated human T lymphocytes produce significantly lower quantities of interferon-gamma and tumor necrosis factor-alpha after stimulation in vitro in the presence of DA-DKP.


METHODS
T lymphocytes activated in the presence of DA-DKP were analyzed by pull-down western blot assay for the activation of the guanosine triphosphatase Rap1 and by quantitative immunoassay for the phosphorylated transcription factors ATF-2 (activating transcription factor-2) and c-jun, which regulate the production of interferon-gamma and tumor necrosis factor-alpha.


RESULTS
Exposure of human T lymphocytes to DA-DKP resulted in increased levels of active Rap1 and decreased activation factors relevant to the T-cell receptor signal transduction pathway and subsequently, decreased phosphorylated ATF-2 and c-jun expression.


CONCLUSIONS
The cyclized N- terminal fragment of human serum albumin, DA-DKP, can modulate the inflammatory immune response through a molecular pathway implicated in T- lymphocyte anergy.
Shimonkevitz
Richard
R
Trauma Research Department, HealthONE Swedish Medical Center, Englewood, Colorado, USA. rickshimon@aol.com
Thomas
Gregory
G
Slone
Denetta Sue
DS
Craun
Michael
M
Mains
Charles
C
Bar-Or
David
D
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D004151:Dipeptides / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D020668:rap GTP-Binding Proteins / Q000378:metabolism
D051698:Activating Transcription Factor 2; D004151:Dipeptides; D016209:Interleukin-8; D016755:Proto-Oncogene Proteins c-jun; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006160:Guanosine Triphosphate; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins; C526103:aspartyl-alanyl-diketopiperazine