Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity.
Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gammac made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gammac had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.
Junttila
Ilkka S
IS
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. junttilai@niaid.nih.gov
Mizukami
Kiyoshi
K
Dickensheets
Harold
H
Meier-Schellersheim
Martin
M
Yamane
Hidehiro
H
Donnelly
Raymond P
RP
Paul
William E
WE
D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*
D053661:Interleukin-13 Receptor alpha1 Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D050800:STAT6 Transcription Factor