Inhibition of interleukin-4-induced class switch recombination by a human immunoglobulin Fc gamma-Fc epsilon chimeric protein.
Immunoglobulin E (IgE) is important in mediating human allergic diseases. We tested the hypothesis that a human Ig Fc gamma-Fc epsilon bifunctional chimeric protein, GE2, would inhibit IgE class switch recombination (CSR) by co-aggregating B-cell CD32 and CD23. Indeed, GE2 directly inhibited epsilon germ-line transcription, subsequent CSR to epsilon and IgE protein production. This CSR inhibition was dependent on CD23 binding and the phosphorylation of extracellular signal-related kinase (ERK), and it was mediated via suppression of interleukin-4-induced STAT6 phosphorylation. Treatment with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase 1 (MAPKK1 (MEK1)) and MEK2 reversed the ability of GE2 to decrease CSR and STAT6 phosphorylation. GE2 stimulation induced ERK phosphorylation, whereas it did not alter the phosphorylation of c-Jun N-terminal kinase or p38 MAPK. The ability of GE2 to block human isotype switching to epsilon, in addition to its already demonstrated ability to inhibit mast cell and basophil function, suggests that it will provide an important novel benefit in the treatment of IgE-mediated diseases.
Yamada
Takechiyo
T
Hart and Louis Laboratory, Division of Clinical Immunology, Department of Medicine, UCLA School of Medicine, California 90095-1680, USA. ymdtkcy@fmsrsa.fukui-med.ac.jp
Zhu
Daocheng
D
Zhang
Ke
K
Saxon
Andrew
A
D015153:Blotting, Western; D002478:Cells, Cultured; D003720:Densitometry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000737:chemistry*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D017455:Receptors, IgE / Q000096:biosynthesis / Q000378:metabolism; D017452:Receptors, IgG / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007135:Immunoglobulin Variable Region; D017455:Receptors, IgE; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D007073:Immunoglobulin E; D012313:RNA; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one