Activation of mitogen-activated protein kinase pathways by angelan in murine macrophages.
In our previous studies, we showed that angelan, a polysaccharide purified from Angelica gigas Nakai, specifically activated macrophages to induce cytokines including inducible nitric oxide synthase (iNOS) which has strong anti-tumor activities [Immunopharmacology, 1999; 43: 1.]. In the present study, we investigated the intracellular signal transduction pathways involved in the angelan-induced iNOS synthesis by murine macrophages. Protein tyrosine phosphorylation was induced within 5 min by angelan, and the blocking of protein tyrosine kinases (PTKs) inhibited down-stream pathways leading to iNOS production in response to angelan. Treament of RAW 264.7 cells with angelan resulted in significant activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38, while stress-activated protein kinase/c-Jun NH2 terminal kinase (SAPK/JNK) was not activated by angelan. The specific p38 inhibitor SB203580 abrogated the angelan-induced iNOS synthesis, whereas the selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK-1) inhibitor PD98059 did not affect the iNOS induction. In conclusion, we demonstrate that PTK and p38 MAPK activation are required to transduce signals leading to iNOS expression in angelan-stimulated murine macrophages.
Jeon
Y J
YJ
Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon, South Korea.
Han
S B
SB
Lee
S H
SH
Kim
H C
HC
Ahn
K S
KS
Kim
H M
HM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D011134:Polysaccharides / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D008070:Lipopolysaccharides; D011134:Polysaccharides; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases