Homodimerization of the human interleukin 4 receptor alpha chain induces Cepsilon germline transcripts in B cells in the absence of the interleukin 2 receptor gamma chain.
The cytokines interleukin (IL)-4 and IL-13 play a critical role in inducing Cepsilon germline transcripts and IgE isotype switching in human B cells. The IL-4 receptor (IL-4R) in B cells is composed of two chains, the IL-4-binding IL-4Ralpha chain, which is shared with the IL-13R, and the IL-2Rgamma (gammac) chain, which is shared with IL-7R, IL-9R, and IL-15R. IL-4 induces Cepsilon germline transcripts and IgE isotype switching in B cells from patients with gammac chain deficiency. Induction of Cepsilon germline transcripts by IL-4 in B cells that lack the gammac chain may involve signaling via the IL-13R. Alternatively, the IL-4Ralpha chain may transduce intracellular signals that lead to Cepsilon gene transcription independently of its association with other chains. We show that ligand-induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 (Jak1) activation, STAT6 activation, and Cepsilon germline transcripts in human B cell line BJAB. Disruption of the Jak1-binding proline-rich Box1 region of IL-4Ralpha abolished signaling by this chimeric receptor. Furthermore, B cells transfected with a chimeric CD8alpha/IL-4Ralpha receptor, which is expressed on the cell surface as a homodimer, constitutively expressed Cepsilon germline transcripts. These results suggest that homodimerization of the IL-4Ralpha chain is sufficient to transduce Jak1-dependent intracellular signals that lead to IgE isotype switching.
Fujiwara
H
H
Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Enders 8th Floor, 300 Longwood Avenue, Boston, MA 02115-5747, USA.
Hanissian
S H
SH
Tsytsykova
A
A
Geha
R S
RS
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000737:chemistry; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D002051:Burkitt Lymphoma; D016827:CD8 Antigens / Q000096:biosynthesis*; D019281:Dimerization; D004789:Enzyme Activation; D004921:Erythropoietin / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D046911:Macromolecular Substances; D051379:Mice; D017467:Receptors, Erythropoietin / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000737:chemistry; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000737:chemistry; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D016827:CD8 Antigens; D046911:Macromolecular Substances; D017467:Receptors, Erythropoietin; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D004921:Erythropoietin; D015847:Interleukin-4