Interleukin-6/soluble interleukin-6 receptor signaling attenuates proliferation and invasion, and induces morphological changes of a newly established pleomorphic malignant fibrous histiocytoma cell line

Am J Pathol. 2004 Aug;165(2):471-80. doi: 10.1016/S0002-9440(10)63312-3.


Pleomorphic malignant fibrous histiocytoma (MFH) is occasionally associated with inflammatory paraneoplastic syndrome (PNS). Recently, we reported that interleukin (IL)-6, one of the candidate cytokines, which induces such systemic inflammatory reaction, may be a tumor-associated factor involved in the pathogenesis and its clinical manifestations of MFH. In the local microenvironment, tumor-induced inflammatory reaction may play a role favoring tumor progression. To clarify the biological relevance of IL-6 in MFH, we established a human MFH cell line, named MIPS-2, derived from a resected specimen of a patient presenting with PNS. In this patient, the serum IL-6 level ran parallel to the disease course: elevated serum IL-6 concentration normalized immediately after radical surgery, and re-elevation occurred on tumor recurrence. MIPS-2 presented pleomorphic appearance, severe nuclear abnormalities with prominent nucleoli, and tumorigenesis in nude mice. MIPS-2 expressed IL-6, IL-6 receptor (IL-6R), and glycoprotein 130 (gp130) but lacked the soluble form of IL-6R (sIL-6R), as determined by flow cytometry and reverse transcriptase-polymerase chain reaction analyses. Stimulation of MIPS-2 with IL-6 combined with exogenous sIL-6R induced phosphorylation of both signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK), decreased cell proliferation, attenuated invasion, and induced morphological changes. Collectively, these data suggested that the IL-6/sIL-6R signaling pathway plays a pivotal role for proliferation, invasion, and morphology of MFH via STAT3 and MAPK pathway as autocrine and/or paracrine manner, and proposed the therapeutic potential for the use of both anti-growth factor and proinflammatory cytokine-targeting strategies to combat devastating MFH.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, CD / metabolism
  • Apoptosis
  • Cell Division / drug effects
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / metabolism
  • Flow Cytometry
  • Histiocytoma, Benign Fibrous / metabolism
  • Histiocytoma, Benign Fibrous / pathology*
  • Humans
  • Interleukin-6 / metabolism*
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Recurrence, Local / pathology
  • Paraneoplastic Syndromes / etiology
  • Paraneoplastic Syndromes / metabolism
  • Paraneoplastic Syndromes / pathology*
  • Phosphorylation
  • Receptors, Interleukin-6 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured


  • Antigens, CD
  • DNA-Binding Proteins
  • IL6ST protein, human
  • Il6st protein, mouse
  • Interleukin-6
  • Membrane Glycoproteins
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • Cytokine Receptor gp130
  • Mitogen-Activated Protein Kinase Kinases