Molecular analysis of human interleukin-9 receptor transcripts in peripheral blood mononuclear cells. Identification of a splice variant encoding for a nonfunctional cell surface receptor.
Genetic studies on mouse models of asthma have identified interleukin-9 (IL9) as a determining factor in controlling bronchial hyperresponsiveness, a hallmark of the disease. Recently, the human IL9 receptor (hIL9R) gene locus has also been implicated in determining susceptibility to bronchial hyperresponsiveness and asthma. In order to evaluate the structure and function of the encoded product, we analyzed receptor transcripts derived from peripheral blood mononuclear cells of 50 unrelated donors. Sequence analysis of the entire coding region identified a splice variant that contains an in frame deletion of a single residue at codon 173 (DeltaQ). This variant could be permanently expressed in a cytokine-dependent murine T-cell line but lacked the ability to induce proliferation in response to human IL9. In situ analyses of cells expressing the wild-type and DeltaQ receptors found both forms to be expressed at the cell surface, but the DeltaQ receptor was unable to bind hIL9 and could not be recognized by N-terminal specific antibodies. These findings demonstrate that hIL9RDeltaQ presents an altered structure and function and suggests its potential role in down-regulating IL9 signaling in effector cells and associated biological processes.
Grasso
L
L
Magainin Institute of Molecular Medicine, Magainin Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania 19462, USA.
Huang
M
M
Sullivan
C D
CD
Messler
C J
CJ
Kiser
M B
MB
Dragwa
C R
CR
Holroyd
K J
KJ
Renauld
J C
JC
Levitt
R C
RC
Nicolaides
N C
NC
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D003001:Cloning, Molecular; D003062:Codon; D005434:Flow Cytometry; D014644:Genetic Variation; D006801:Humans; D016906:Interleukin-9 / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection
D003062:Codon; C508045:IL9R protein, human; D016906:Interleukin-9; D018123:Receptors, Interleukin; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins