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Am J Physiol Cell Physiol (April 9, 2003). doi:10.1152/ajpcell.00026.2003
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Submitted on January 16, 2003
Accepted on April 8, 2003

Janus Kinase 2 is Involved in Lipopolysaccharide-Induced Activation of Macrophages

Shu Okugawa1, Yasuo Ota1*, Takatoshi Kitazawa1, Kuniko Nakayama1, Shintaro Yanagimoto1, Kunihisa Tsukada1, Miki Kawada1, and Satoshi Kimura1

1 Department of Infectious Disease, Graduate School of Medicine, The Universtiy of Tokyo, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: yasuota-tky{at}umin.ac.jp.

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 and NF-{kappa}B. Activation of protein tyrosine kinases 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 2 (JAK2) is tyrosine-phosphorylated immediately after LPS stimulation. Anti-TLR4 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 PI3K via LPS stimulation. Pharmacological inhibition of the kinase activity of PI3K with LY294002 decreases the phosphorylation of JNK. Finally, we show that JAK2 is involved in the production of IL-1{beta} and IL-6. PI3K and JNK are also important for the production of IL-1{beta}. 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-1{beta} via the PI3K/JNK cascade. Thus, JAK2 plays a pivotal role in LPS-induced signaling in macrophages.




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