IL-1beta augments TNF-alpha-mediated inflammatory responses from lung epithelial cells

J Interferon Cytokine Res. 2009 May;29(5):273-84. doi: 10.1089/jir.2008.0076.


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.

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism
  • Chemokine CXCL2 / genetics
  • Chemokine CXCL2 / metabolism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-1beta / pharmacology*
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / pathology*
  • Metalloproteases / metabolism
  • Mice
  • RNA, Messenger / genetics
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Chemokine CXCL1
  • Chemokine CXCL2
  • Interleukin-1beta
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Metalloproteases