title: Differences in signaling pathways by IL-1beta and IL-18.
abstract: 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-gamma 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 beta chain and responded to IL-18 with increased production of IL-1alpha, 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-1beta induced the expression of the NF-kappaB-reporter gene and was suppressed by competitive inhibition of NF-kappaB binding, IL-18 responses were weak or absent. In contrast to IL-1beta, IL-18 also did not activate degradation of the NF-kappaB 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-1beta 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-kappaB, which may explain the absence of COX-2 and the failure of IL-18 to cause fever.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Jae-Kwon
authors.initials: JK
authors.lastname: Lee
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Reznikov
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D051546:Cyclooxygenase 2; D018076:DNA, Complementary / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D005334:Fever / Q000209:etiology; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018076:DNA, Complementary; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D016209:Interleukin-8; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone