Tumour necrosis factor-alpha production stimulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease.
Summaryand interleukin (IL)-12 by dendritic cells (DC) from patients with Crohn's disease. TNF-alpha concentration was increased significantly when DC from Crohn's disease were stimulated with HSP70 or CD40L and this was associated with signalling by the extracellular signal regulated kinase (ERK) 1/2 and p38 mitogen activated protein (MAP) kinase pathway. IL-12 production was also increased when DC were stimulated with HSP70. Cells eluted from inflamed intestinal mucosa from Crohn's disease, stimulated with HSP70, CD40L or lipopolysaccharide produced significantly greater TNF-alpha and IL-12 concentrations than cells from uninflamed mucosa. Significant inhibition of TNF-alpha production was demonstrated when DC from peripheral blood mononuclear cells or cells eluted from intestinal mucosa of Crohn's disease were treated with either the HSP70 inhibitory peptide (aa 457-496) or peptides derived from CD40 and CD40L. These inhibitory peptides target the CD40-CD40L and the emerging CD40-HSP70 co-stimulatory pathway. Our findings offer a novel strategy to prevent excessive production of TNF-alpha in Crohn's disease.
Whittall
T
T
Mucosal Immunology Unit and Dept. of Oral Immunology, Guy's, King's and St Thomas' Medical and Dental Schools, Guy's Hospital, London SE1 9RT, UK.
Wang
Y
Y
Kelly
C G
CG
Thompson
R
R
Sanderson
J
J
Lomer
M
M
Soon
S Y
SY
Bergmeier
L A
LA
Singh
M
M
Lehner
T
T
D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D003093:Colitis, Ulcerative / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal; D018664:Interleukin-12 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D019013:CD40 Antigens; D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12