Dexamethasone and FK506 inhibit expression of distinct subsets of chemokines in human mast cells.
Mast cells produce a large amount of several chemokines after cross-linking of FcepsilonRI and participate in the pathogenesis of allergic diseases. The objective of this study was to comprehensively investigate FcepsilonRI-mediated chemokine induction in human mast cells and the effect of a corticosteroid (dexamethasone) and a calcineurin inhibitor (FK506). Human peripheral blood-derived mast cells were stimulated with anti-IgE Ab in the presence of dexamethasone or FK506. Gene expression profiles were evaluated using GeneChip and confirmed by real-time PCR, and chemokine concentrations were measured by cytometric bead arrays and ELISA. Expression of eight chemokines was significantly induced in mast cells by anti-IgE stimulation. Induction of CCL2, CCL7, CXCL3, and CXCL8 by anti-IgE was significantly inhibited by dexamethasone but was enhanced by FK506. In contrast, induction of CCL1, CCL3, CCL4, and CCL18 was significantly inhibited by FK506 but, with the exception of CCL1, was enhanced by dexamethasone. Combination of dexamethasone and FK506 suppressed production of all chemokines by anti-IgE stimulation. Studies using protease inhibitors indicate that mast cell proteases may degrade several of the chemokines. These results suggest that corticosteroids and calcineurin inhibitors inhibit expression of distinct subsets of chemokines, and a combination of these drugs almost completely suppresses the induction of all chemokine genes in human mast cells in response to FcepsilonRI-dependent stimulation. This implies that a combination of a corticosteroid and a calcineurin inhibitor may be more effective than each single agent for the treatment of allergic diseases in which mast cell-derived chemokines play a major role.
Kato
Atsushi
A
Department of Medicine, Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Chustz
Regina T
RT
Ogasawara
Takahisa
T
Kulka
Marianna
M
Saito
Hirohisa
H
Schleimer
Robert P
RP
Matsumoto
Kenji
K
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D017455:Receptors, IgE / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000906:Antibodies; D065095:Calcineurin Inhibitors; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D007166:Immunosuppressive Agents; D017455:Receptors, IgE; D007073:Immunoglobulin E; D003907:Dexamethasone; D016559:Tacrolimus