IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis.
Besides its function as a growth factor, IL-2 induces beta2-integrin-dependent, homotypic adhesion of IL-2R-positive T cells. In this study, we investigated how IL-2R are functionally and biochemically linked to the beta2-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2-induced adhesion. Herbimycin A and genestein, inhibitors of protein tyrosine kinases, inhibit cytokine-induced adhesion and mitogenesis in parallel, whereas cytochalasin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mitogenesis. IL-2R ligation rapidly (<5 min) induces tyrosine phosphorylation of several proteins, the most prominent being signal transducer and activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125). Wortmannin, LY294002, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation of an as yet unidentified protein of 125 kDa.
Nielsen
M
M
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
Svejgaard
A
A
Skov
S
S
Dobson
P
P
Bendtzen
K
K
Geisler
C
C
Odum
N
N
D018821:CD18 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D003572:Cytochalasins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology; D053616:Janus Kinase 3; D008970:Molecular Weight; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011090:Polyenes / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020123:Sirolimus
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D002867:Chromones; D003572:Cytochalasins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D015851:Interleukin-7; D009025:Morpholines; D010750:Phosphoproteins; D011090:Polyenes; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C007215:cytochalasin E; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D020123:Sirolimus