title: IL-1beta augments TNF-alpha-mediated inflammatory responses from lung epithelial cells.
abstract: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) mediate the development of numerous inflammatory lung diseases. Since IL-1beta is typically activated in situations where TNF-alpha is produced, it was hypothesized that IL-1beta alters TNF-alpha-induced proinflammatory epithelial cell function by altering TNF receptor shedding and surface abundance. In this study, the impact of IL-1beta on TNF-alpha-mediated chemokine production as well as TNF receptor surface expression and shedding were investigated from mouse pulmonary epithelial cells (MLE-15). Interleukin-1beta rapidly and persistently enhanced soluble and surface TNFR2. These effects were dependent on TNFR1 expression. TNFR2 small-interfering RNA (siRNA) shifted IL-1beta responses, significantly increasing surface and shed TNFR1 implying IL-1beta selectively modifies TNF receptors depending on cellular receptor composition. mRNA expression of both receptors was unaltered by IL-1beta up to 24 h or in combination with TNF-alpha indicating effects were post-transcriptional. Interleukin-1beta pretreatment enhanced TNF-alpha-induced macrophage inflammatory protein (MIP)-2 and KC mRNA expression as well as MIP-2 and KC protein levels at the same time point analyzed. Experiments utilizing siRNA against the TNF receptors and a TNFR1 neutralizing antibody demonstrated TNF-alpha induced MIP-2 through TNFR1, whereas both receptors may have contributed to KC production. These data suggest IL-1beta modulates TNF-alpha-mediated inflammatory lung diseases by enhancing epithelial cell TNF receptor surface expression.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA. Sara_Saperstein@urmc.rochester.edu
authors.forename: Sara
authors.initials: S
authors.lastname: Saperstein
authors.forename: Linlin
authors.initials: L
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Oakes
authors.forename: Gloria
authors.initials: G
authors.lastname: Pryhuber
authors.forename: Jacob
authors.initials: J
authors.lastname: Finkelstein
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D053583:Interleukin-1beta; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D045726:Metalloproteases