Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-gamma-induced CXCL10 production by immature human dendritic cells.
Effector memory T helper 2 (Th2) cells that accumulate in target organs (i.e. skin or bronchial mucosa) have a central role in the pathogenesis of allergic disorders. To date, the factors that selectively trigger local production of Th2-attracting chemokines remain poorly understood. In mucosa, at the sites of allergen entry, immature dendritic cells (DC) are in close contact with mast cells. Histamine and prostaglandin E2 (PGE2) are two mediators released by allergen-activated mast cells that favour the polarization of maturing DC into Th2-polarizing cells. We analysed here the effects of histamine and PGE2 on the prototypic, Th2-(CCL17, CCL22) versus Th1-(CXCL10) chemokine production by human DC. We report that histamine and PGE2 dose-dependently up-regulate CCL17 and CCL22 by monocyte-derived immature DC. These effects were potentiated by tumour necrosis factor-alpha, still observed in the presence of the Th1-cytokine interferon-gamma (IFN-gamma) and abolished by the immunomodulatory cytokine interleukin-10. In addition, histamine and PGE2 down-regulated IFN-gamma-induced CXCL10 production by monocyte-derived DC. These properties of histamine and PGE2 were observed at the transcriptional level and were mediated mainly through H2 receptors for histamine and through EP2 and EP4 receptors for PGE2. Finally, histamine and PGE2 also up-regulated CCL17 and CCL22 and decreased IFN-gamma-induced CXCL10 production by purified human myeloid DC. In conclusion, these data show that, in addition to polarizing DC into mature cells that promote naïve T-cell differentiation into Th2 cells, histamine and PGE2 may act on immature DC to trigger local Th2 cell recruitment through a selective control of Th1/Th2-attracting chemokine production, thereby contributing to maintain a microenvironment favourable to persistent immunoglobulin E synthesis.
Immunology and Allergology Laboratory, University Hospital of Angers, University of Angers, Angers, France.
Anne
A
McIlroy
Gersende
G
Caron
Simon
S
Blanchard
Isabelle
I
Frémaux
Dorothée
D
Duluc
Yves
Y
Delneste
Alain
A
Chevailler
Pascale
P
Jeannin
D002478:Cells, Cultured; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D006632:Histamine / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology; D011458:Prostaglandins E / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D011970:Receptors, Histamine H2 / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018418:Th2 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
C106230:CCL17 protein, human; C515482:CCL22 protein, human; C114753:CXCL10 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D011458:Prostaglandins E; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D007371:Interferon-gamma