Genetic control of interleukin-4-induced activation of the human signal transducer and activator of transcription 6 signaling pathway.
The interleukin (IL)-4-induced Stat6 signaling pathway is active in a variety of cell types, including immune cells and cancer cells, and plays an important role in the regulation of gene expression, such as CD23 and major histocompatibility complex class II. Using a semiquantitative gel shift assay in which nuclear Stat6 activities were scored, three Stat6 activation phenotypes were defined as Stat6(high) (intense banding), Stat6(low) (medium intensity banding), and Stat6(null) (very low to no discernible banding). These Stat6 phenotypes correlated well with levels of CD23 expression, but not with those of human leukocyte antigen-DR cell-surface display. Pedigree analyses revealed a Mendelian inheritance pattern that can be explained by two STAT6 Pathway (STAT6P) activation genotypes, which we term A and a, where STAT6P*A determines an active Stat6 signaling and STAT6P*a determines an inactive Stat6 signaling, with incomplete dominance. Total Stat6 protein levels failed to correlate with the above Stat6 phenotypes allowing us to propose that IL-4-induced Stat6 signaling is a polygenic quantitative trait regulated by a collection of several contributing genetic loci that functionally interact. The Stat6(null) phenotype may result from a defect in Stat6 signaling, which has important implications with respect to the pathogenesis of cancer and Th1/Th2 cytokine imbalance in autoimmune diseases in general.
Zhang
Wen Jie
WJ
Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. wzhang@psu.edu
Koltun
Walter A
WA
Tilberg
Anna F
AF
Thompson
Jennifer L
JL
Chorney
Michael J
MJ
D002461:Cell Line, Transformed; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D040641:Quantitative Trait Loci; D017455:Receptors, IgE / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*
D017455:Receptors, IgE; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4