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.
Kruse
Susanne
S
University Children's Hospital, University of Freiburg, Mathildenstr, 1, 79106 Freiburg, Germany. kruse.susanne@mh-hannover.de <kruse.susanne@mh-hannover.de>
Braun
Sandra
S
Deichmann
Klaus A
KA
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