IL-2R beta agonist P1-30 acts in synergy with IL-2, IL-4, IL-9, and IL-15: biological and molecular effects.
From the sequence of human IL-2 we have recently characterized a peptide (p1-30), which is the first IL-2 mimetic described. P1-30 covers the entire alpha helix A of IL-2 and spontaneously folds into a alpha helical homotetramer mimicking the quaternary structure of a hemopoietin. This neocytokine interacts with a previously undescribed dimeric form of the human IL-2 receptor beta-chain likely to form the p1-30 receptor (p1-30R). P1-30 acts as a specific IL-2Rbeta agonist, selectively inducing activation of CD8 and NK lymphocytes. From human PBMC we have also shown that p1-30 induces the activation of lymphokine-activated killer cells and the production of IFN-gamma. Here we demonstrate the ability of p1-30 to act in synergy with IL-2, -4, -9, and -15. These synergistic effects were analyzed at the functional level by using TS1beta, a murine T cell line endogenously expressing the common cytokine gamma gene and transfected with the human IL-2Rbeta gene. At the receptor level, we show that expression of human IL-2Rbeta is absolutely required to obtain synergistic effects, whereas IL-2Ralpha specifically impedes the synergistic effects obtained with IL-2. The results suggest that overexpression of IL-2Ralpha inhibits p1-30R formation in the presence of IL-2. Finally, concerning the molecular effects, although p1-30 alone induces the antiapoptotic molecule bcl-2, we show that it does not influence mRNA expression of c-myc, c-jun, and c-fos oncogenes. In contrast, p1-30 enhances IL-2-driven expression of these oncogenes. Our data suggest that p1-30R (IL-2Rbeta)(2) and intermediate affinity IL-2R (IL-2Rbetagamma), when simultaneously expressed at the cell surface, may induce complementary signal transduction pathways and act in synergy.
Eckenberg
R
R
Unité d'Immunogénétique Cellulaire, Institut Pasteur, Paris, France.
Moreau
J L
JL
Melnyk
O
O
Thèze
J
J
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D003470:Culture Media / Q000378:metabolism; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D016906:Interleukin-9 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018716:Molecular Mimicry / Q000276:immunology; D010446:Peptide Fragments / Q000819:agonists* / Q000502:physiology; D011519:Proto-Oncogenes / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000819:agonists* / Q000096:biosynthesis / Q000502:physiology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D003470:Culture Media; D019409:Interleukin-15; D007376:Interleukin-2; D016906:Interleukin-9; D007378:Interleukins; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D015847:Interleukin-4