Inhibition of lymphocyte kinase Lck and phosphatidylinositol 3-kinase by a novel immunosuppressant, lymphostin.
Lck is a Src-family tyrosine kinase that is expressed predominantly in T cells, where it plays important roles in T-cell activation. Lymphostin was isolated from Streptomyces sp. as an inhibitor of Lck. As previously reported, lymphostin inhibited Lck (IC50 0.05 microM) and the mixed lymphocyte reaction (IC50 0.009 microM). We have now examined the mechanism of inhibition by lymphostin. Lymphostin inhibited protein-tyrosine kinase activity in Jurkat T cells, demonstrating the effectiveness of the compound at the cellular level. Furthermore, lymphostin suppressed delayed-type hypersensitivity in mice. However, the inhibitory activity against Lck at the cellular level was weaker than that against the mixed lymphocyte reaction. Thus, we examined the effects of lymphostin on other kinases. Interestingly, lymphostin also inhibited phosphatidylinositol 3-kinase (IC50 0.001 microM). Consequently, we conclude that lymphostin inhibits the mixed lymphocyte reaction and delayed-type hypersensitivity not only through the blockade of Lck, but through the blockade of phosphatidylinositol 3-kinase as well.
Nagata
Hiroyuki
H
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co, Ltd, Machida-shi, Japan. hiroyuki.nagata@kyowa.co.jp
Yano
Hiroshi
H
Sasaki
Kimihito
K
Sato
Soichiro
S
Nakanishi
Satoshi
S
Takahashi
Isami
I
Tamaoki
Tatsuya
T
D000818:Animals; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019000:Phosphotyrosine; D011758:Pyrroles; D011804:Quinolines; C114118:lymphostin LK6-A