Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages.
The mechanisms by which lipopolysaccharide (LPS) is recognized, and how such recognition leads to innate immune responses, are poorly understood. Stimulation with LPS induces the activation of a variety of proteins, including mitogen-activated protein kinases (MAPKs) and NF-kappaB. Activation of protein tyrosine kinases (PTKs) is also necessary for a number of biological responses to LPS. We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK). Both the JAK inhibitor AG490 and the kinase-deficient JAK2 protein reduce the phosphorylation of JNK and phosphatidylinositol 3-kinase (PI3K) via LPS stimulation. Pharmacological inhibition of the kinase activity of PI3K with LY-294002 decreases the phosphorylation of JNK. Finally, we show that JAK2 is involved in the production of IL-1beta and IL-6. PI3K and JNK are also important for the production of IL-1beta. These results suggest that LPS induces tyrosine phosphorylation of JAK2 via TLR4 and that JAK2 regulates phosphorylation of JNK mainly through activation of PI3K. Phosphorylation of JAK2 via LPS stimulation is important for the production of IL-1beta via the PI3K/JNK cascade. Thus JAK2 plays a pivotal role in LPS-induced signaling in macrophages.
Okugawa
Shu
S
Department of Infectious Disease, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Ota
Yasuo
Y
Kitazawa
Takatoshi
T
Nakayama
Kuniko
K
Yanagimoto
Shintaro
S
Tsukada
Kunihisa
K
Kawada
Miki
M
Kimura
Satoshi
S
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D007378:Interleukins / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D053614:Janus Kinase 2; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000906:Antibodies; D004791:Enzyme Inhibitors; D007378:Interleukins; D048031:JNK Mitogen-Activated Protein Kinases; D053614:Janus Kinase 2; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C507926:Jak2 protein, mouse