TY - JOUR
T1 - Differences in signaling pathways by IL-1β and IL-18
AU - Lee, Jae Kwon
AU - Kim, Soo Hyun
AU - Lewis, Eli C.
AU - Azam, Tania
AU - Reznikov, Leonid L.
AU - Dinarello, Charles A.
PY - 2004/6/8
Y1 - 2004/6/8
N2 - IL-1 and IL-18 are members of the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Although several biological properties overlap for these cytokines, differences exist. IL-18 uniquely induces IFN-γ from T lymphocytes and natural killer cells but does not cause fever, whereas fever is a prominent characteristic of IL-1 in humans and animals. In the present study, human epithelial cells were stably transfected with the IL-18 receptor β chain and responded to IL-18 with increased production of IL-1α, IL-6, and IL-8. Five minutes after exposure to either cytokine, phosphorylation of mitogen activated protein kinase (MAPK) p38 was present; specific inhibition of p38 MAPK reduced IL-18 activity to background levels. Whereas IL-1β induced the expression of the NF-κB-reporter gene and was suppressed by competitive inhibition of NF-κB binding, IL-18 responses were weak or absent. In contrast to IL-1β, IL-18 also did not activate degradation of the NF-κB inhibitor. After 4 h, both cytokines induced comparable levels of mRNA for the chemokine IL-8 but, in the same cells, steady-state levels of cyclooxygenase (COX)-2 mRNA were high after IL-1β but low or absent after IL-18. After 30 h, IL-18-induced COX-2 appeared in part to be IL-1 dependent. Similarly, low levels of prostaglandin E2 were measured in IL-18-stimulated A549 cells and freshly obtained primary human monocytes and mouse macrophages. We conclude that in epithelial cells, IL-18 signal transduction is primarily via the MAPK p38 pathway rather than NF-κB, which may explain the absence of COX-2 and the failure of IL-18 to cause fever.
AB - IL-1 and IL-18 are members of the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Although several biological properties overlap for these cytokines, differences exist. IL-18 uniquely induces IFN-γ from T lymphocytes and natural killer cells but does not cause fever, whereas fever is a prominent characteristic of IL-1 in humans and animals. In the present study, human epithelial cells were stably transfected with the IL-18 receptor β chain and responded to IL-18 with increased production of IL-1α, IL-6, and IL-8. Five minutes after exposure to either cytokine, phosphorylation of mitogen activated protein kinase (MAPK) p38 was present; specific inhibition of p38 MAPK reduced IL-18 activity to background levels. Whereas IL-1β induced the expression of the NF-κB-reporter gene and was suppressed by competitive inhibition of NF-κB binding, IL-18 responses were weak or absent. In contrast to IL-1β, IL-18 also did not activate degradation of the NF-κB inhibitor. After 4 h, both cytokines induced comparable levels of mRNA for the chemokine IL-8 but, in the same cells, steady-state levels of cyclooxygenase (COX)-2 mRNA were high after IL-1β but low or absent after IL-18. After 30 h, IL-18-induced COX-2 appeared in part to be IL-1 dependent. Similarly, low levels of prostaglandin E2 were measured in IL-18-stimulated A549 cells and freshly obtained primary human monocytes and mouse macrophages. We conclude that in epithelial cells, IL-18 signal transduction is primarily via the MAPK p38 pathway rather than NF-κB, which may explain the absence of COX-2 and the failure of IL-18 to cause fever.
UR - http://www.scopus.com/inward/record.url?scp=2942588523&partnerID=8YFLogxK
U2 - 10.1073/pnas.0402800101
DO - 10.1073/pnas.0402800101
M3 - Article
AN - SCOPUS:2942588523
SN - 0027-8424
VL - 101
SP - 8815
EP - 8820
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
ER -