Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: involvement of ERK, JNK, AP-1, and NF-kappaB

J Cell Physiol. 2010 Aug;224(2):516-26. doi: 10.1002/jcp.22153.


Interleukin-1beta (IL-1beta) has been shown to induce the expression of adhesion molecules on various cell types and contributes to inflammatory responses. However, the molecular mechanisms by which IL-1beta induced intercellular adhesion molecule (ICAM)-1 expression remain unclear in human rheumatoid arthritis synovial fibroblasts (RASFs). Here, we demonstrated that IL-1beta induces ICAM-1 gene expression via the de novo protein synthesis through transcription and translation, which is attenuated by pretreatment with actinomycin D and cycloheximide, respectively. IL-1beta-induced ICAM-1 expression, extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) phosphorylation, AP-1 activation, and nuclear factor-kappaB (NF-kappaB) p65 translocation were attenuated by the inhibitors of MEK1/2 (U0126), JNK (SP600125), AP-1 (tanshinone IIA), and NF-kappaB (helenalin) or transfection with respective short hairpin RNA plasmids. Moreover, IL-1beta-stimulated NF-kappaB p65 translocation was blocked by helenalin, but not by U0126 or SP600125, revealing that MAPKs and NF-kappaB pathways were independent on these responses. IL-1beta-stimulated AP-1 activation was blocked by U0126 or SP600125, revealing that ERK and JNK linked to AP-1 on these responses. IL-1beta-stimulated ICAM-1 gene expression was attenuated by pretreatment with U0126, SP600125, tanshinone IIA, or helenalin, revealed by ICAM-1 promoter assay and real-time RT-PCR analysis. Finally, up-regulation of ICAM-1 enhanced the adhesion of leukocytes to RASFs exposed to IL-1beta. These results suggest that in human RASFs, activation of ERK, JNK, AP-1, and NF-kappaB are essential for IL-1beta-induced ICAM-1 expression and leukocyte adhesion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / pathology
  • Cell Adhesion / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology*
  • Fibroblasts / pathology
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Interleukin-1beta / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Leukocytes / cytology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects
  • Synovial Membrane / drug effects
  • Synovial Membrane / enzymology
  • Synovial Membrane / pathology
  • Transcription Factor AP-1 / metabolism*


  • Interleukin-1beta
  • NF-kappa B
  • Transcription Factor AP-1
  • Intercellular Adhesion Molecule-1
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases