PMID- 10233717
OWN - NLM
STAT- MEDLINE
DCOM- 19990721
LR  - 20190513
IS  - 0019-2805 (Print)
IS  - 1365-2567 (Electronic)
IS  - 0019-2805 (Linking)
VI  - 96
IP  - 3
DP  - 1999 Mar
TI  - The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are 
      associated with atopy and influence the signal transduction.
PG  - 365-71
AB  - Interleukin-4 (IL-4) plays a major role in immunoglobulin E (IgE) production. Its 
      signal is conferred to effector cells through binding to the alpha chain of the 
      IL-4 receptor (IL-4Ralpha). We present further evidence for polymorphisms in the 
      IL-4Ralpha gene having an effect on IgE regulation. For two of four common 
      polymorphisms, S503P and Q576R, we found an association with lowered total IgE 
      concentrations (P=0.0008 if occurring together). The polymorphism S503P has not 
      yet been described and is located within the I4R motif of the receptor. In vitro 
      analyses using synthetic peptides of this region showed that the tyrosine kinase 
      Janus kinase 1 (JAK1), as well as IRS-1 and IRS-2 bind to the I4R motif 
      irrespective of the polymorphism or a tyrosine phosphorylation. In vivo 
      immunoassays using T cells of four different groups of individuals (S503/Q576; 
      P503/Q576; S503/R576; P503/R576) revealed that only in case of both polymorphisms 
      the phosphorylation of IRS-1 and IRS-2, but not JAK1 was increased. We found no 
      binding of STAT6 to the I4R synthetic peptides; however, the phosphorylation was 
      reduced in the presence of any of the two polymorphisms, including P503 alone. We 
      discuss possible conformational changes of the receptor leading to the observed 
      effects on the phosphorylation status of IRS-1, IRS-2 and STAT6, in addition to 
      previous findings that Q576R alters STAT6 binding. We conclude that P503 and R576 
      influence the signal transduction pathways through the IL-4Ralpha, an effect that 
      is magnified by the presence of both polymorphisms. This could explain the 
      observed association effects with lowered total IgE concentrations.
FAU - Kruse, S
AU  - Kruse S
AD  - University Children's Hospital, University of Freiburg, Freiburg, Germany.
FAU - Japha, T
AU  - Japha T
FAU - Tedner, M
AU  - Tedner M
FAU - Sparholt, S H
AU  - Sparholt SH
FAU - Forster, J
AU  - Forster J
FAU - Kuehr, J
AU  - Kuehr J
FAU - Deichmann, K A
AU  - Deichmann KA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Immunology
JT  - Immunology
JID - 0374672
RN  - 0 (Receptors, Interleukin-4)
RN  - 37341-29-0 (Immunoglobulin E)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Alleles
MH  - Cell Culture Techniques
MH  - Child
MH  - Humans
MH  - Hypersensitivity, Immediate/*genetics/immunology
MH  - Immunoglobulin E/blood
MH  - Linkage Disequilibrium
MH  - Phosphorylation
MH  - Polymerase Chain Reaction
MH  - *Polymorphism, Genetic
MH  - Receptors, Interleukin-4/*genetics
MH  - Signal Transduction/*genetics/immunology
PMC - PMC2326760
EDAT- 1999/05/08 00:00
MHDA- 1999/05/08 00:01
PMCR- 2000/03/01
CRDT- 1999/05/08 00:00
PHST- 1999/05/08 00:00 [pubmed]
PHST- 1999/05/08 00:01 [medline]
PHST- 1999/05/08 00:00 [entrez]
PHST- 2000/03/01 00:00 [pmc-release]
AID - imm705 [pii]
AID - 10.1046/j.1365-2567.1999.00705.x [doi]
PST - ppublish
SO  - Immunology. 1999 Mar;96(3):365-71. doi: 10.1046/j.1365-2567.1999.00705.x.