Distinct signal transduction processes by IL-4 and IL-13 and influences from the Q551R variant of the human IL-4 receptor alpha chain.
BACKGROUND
Although IL-4 and IL-13 share the IL-13 receptor, IL-13 exhibits unique functions. To elicit the cellular basis of these differences, signal transduction processes have been compared. Additionally, the role of the IL-4 receptor alpha (IL-4Ralpha) variant Q551R was investigated.


METHODS
Peripheral blood mononuclear cells from donors were stimulated with IL-4 and IL-13. The phosphorylation status of effector substrates was detected by immunostaining. Binding of SHP-2 to IL-4Ralpha was investigated by using synthetic peptides.


RESULTS
SHP-2 bound IL-4Ralpha synthetic peptide; this binding was reduced in the presence of the R551 variant. Stimulation with IL-4 increased SHP-1 phosphorylation, however, stimulation with IL-13 increased SHP-2 phosphorylation. PI3-kinase phosphorylation was elevated following stimulation with IL-13 in all individuals and with IL-4 only in R551 individuals. Jak1, Tyk2 and IRS-2 signals were reduced after IL-13 stimulation in Q551 individuals. STAT3 phosphorylation was markedly increased in R551 individuals, following stimulation with both IL-4 and IL-13. However, STAT3 was only detected immediately in nuclear extracts from variant individuals after stimulation with IL-13; in wildtype individuals STAT3 was only detected after IL-4 treatment.


CONCLUSIONS
IL-4 and IL-13 appear to promote distinct signal transduction cascades. SHP-1 seems to be predominately activated by IL-4 and to influence the PI3-kinase, in contrast, SHP-2 seems to be predominately activated by IL-13 and to influence Jak1, Tyk2 and IRS-2. Both phosphatases control STAT3. In the presence of the variant R551, SHP-1/2 activation is reduced and signal transduction is altered. STAT3 signaling appears be further regulated on the level of nuclear translocation.
University Children's Hospital, University of Freiburg, Mathildenstr, 1, 79106 Freiburg, Germany. kruse.susanne@mh-hannover.de <kruse.susanne@mh-hannover.de>
Susanne
S
Kruse
Sandra
S
Braun
Klaus A
KA
Deichmann
D001120:Arginine / Q000235:genetics*; D002478:Cells, Cultured; D014644:Genetic Variation / Q000502:physiology*; D005973:Glutamine / Q000235:genetics*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics* / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D018793:Interleukin-13; D021122:Protein Subunits; D019948:Receptors, Interleukin-4; D005973:Glutamine; D015847:Interleukin-4; D001120:Arginine