Interleukin-18 induces activation and association of p56(lck) and MAPK in a murine TH1 clone.
Interleukin-18 (IL-18) was identified as an inducer of interferon-gamma (IFN-gamma) production by stimulated T cells. In this study, we used an ovalbumin-responsive murine Th1 clone (OVA#4), in which DNA synthesis was reportedly enhanced after IL-18 treatment in the presence of a non-mitogenic TCR/CD3 stimulus, to examine signal transduction pathways. In the presence of the stimulus, IL-18 induced the appearance of tyrosine-phosphorylated proteins and herbimycin A inhibited DNA synthesis. It is suggested that protein tyrosine kinase (PTK) mediated signaling is induced by IL-18. Specifically, IL-18 induced phosphorylation of phosphorylates p56(lck) (LCK) and mitogen-activated protein kinase (MAPK). IL-18 alone induced the kinase activities of both LCK and MAPK, and the activities were increased by the TCR/CD3 stimulus. Simultaneously, IL-18 induced the association of LCK with MAPK and this was also increased by the TCR/CD3 stimulus. The activation of the LCK-MAPK pathway correlated with enhanced DNA synthesis in OVA#4 cells. These results suggest that the LCK-MAPK pathway is involved in IL-18 signaling and that IL-18 may play an important role in modification of TCR/CD3-mediated response.
Tsuji-Takayama
K
K
Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan. fujih@po.harenet.or.jp
Matsumoto
S
S
Koide
K
K
Takeuchi
M
M
Ikeda
M
M
Ohta
T
T
Kurimoto
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016227:Benzoquinones; D017252:CD3 Complex / Q000276:immunology / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002999:Clone Cells; D016207:Cytokines / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020382:Interleukin-18; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D020382:Interleukin-18; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases