on January 10, 2008
Published online before print January 10, 2008, doi: 10.1161/ATVBAHA.107.160580
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 2, 2007
Accepted on December 27, 2007
In Human Macrophages the Complement Component c5a Induces the Expression of Oncostatin M via AP-1 Activation
Stefan P. Kastl ;
From the Department of Internal Medicine II, Division of Cardiology (S.P.K., W.S.S., C.K., K.M.K., G.R., G.M., J.W.), Medical University of Vienna, Austria; the Department of Vascular Biology and Thrombosis Research (T.A., V.N.B., M.H., R.d.M.), Medical University of Vienna, Austria; the Department of Internal Medicine I, Division of Hematology and Hemostaseology (P.V.), Medical University of Vienna, Austria; 1st Department of General and Vascular Surgery (A.A., G.W.H.), Wilhelminenhospital, Vienna, Austria; the Department of Veterans Affairs Medical Center (Y.M.), Medical Research Service, Boise, Idaho; 3rd Department of Medicine (K.H.), Wilhelminenhospital, Vienna, Austria; and Ludwig Boltzmann Cluster for Cardiovascular Research (J.W), Vienna, Austria.
* To whom correspondence should be addressed. E-mail: johann.wojta{at}meduniwien.ac.at.
Objective—Macrophages produce the cytokine oncostatin M (OSM), which beside other functions is also involved in inflammation. The complement component C5a mobilizes and activates these cells at inflammatory sites. We examined the effect of C5a on OSM production in human monocytes and in human monocyte-derived macrophages.
Methods and Results—For macrophage transformation peripheral blood monocytes were cultivated for 8 to 10 days in the presence of human serum. C5a significantly increased in these cells OSM antigen as determined by specific ELISA and mRNA as quantitated by real-time polymerase chain reaction in these cells as well as in plaque macrophages. This effect was blocked by antibodies against the receptor C5aR/CD88 and by pertussis toxin. The C5a-induced phosphorylation of p38 and JNK and the C5a-induced increase in OSM production in macrophages was abolished by 2 p38 inhibitors and by a JNK inhibitor. Furthermore C5a increased the nuclear translocation of c-fos and c-jun. Using different OSM promoter deletion mutant constructs we show that the putative AP-1 element is responsible for activation of OSM promoter activity by C5a.
Conclusion—Our data establish a link between the complement system and the gp130 receptor cytokine family with possible implications for the pathology of inflammatory diseases.