The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.
To understand the molecular bases for cytokine redundancy and pleiotropy, we have compared the Stat proteins activated in peripheral blood lymphocytes (PBLs) by cytokines with shared and distinct actions. Interleukin-2 (IL-2) rapidly activated Stat5 in fresh PBL, and Stat3 and Stat5 in preactivated PBL. IL-7 and IL-15 induced the same complexes as IL-2, a feature explained by the existence of similar tyrosine-phosphorylated motifs in the cytoplasmic domains of IL-2R beta and IL-7R that can serve as docking sites for Stat proteins. IL-13 Induced the same complexes as IL-4, a finding explained by our studies implicating IL-4R as a shared component of the receptors. These studies demonstrate that a single cytokine can activate different combinations of Stat proteins under different physiological conditions, and also indicate two mechanisms by which distinct cytokines can activate the same Stat protein.
Lin
J X
JX
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.
Migone
T S
TS
Tsang
M
M
Friedmann
M
M
Weatherbee
J A
JA
Zhou
L
L
Yamauchi
A
A
Bloom
E T
ET
Mietz
J
J
John
S
S
D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D019409:Interleukin-15; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008894:Milk Proteins; D008969:Molecular Sequence Data; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis*
D015342:DNA Probes; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; D008894:Milk Proteins; D018123:Receptors, Interleukin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D015847:Interleukin-4