Tumor necrosis factor alpha blockade treatment down-modulates the increased systemic and local expression of Toll-like receptor 2 and Toll-like receptor 4 in spondylarthropathy

Arthritis Rheum. 2005 Jul;52(7):2146-58. doi: 10.1002/art.21155.


Objective: Abnormal host defense against pathogens has been implicated in the pathogenesis of spondylarthropathy (SpA), a disease characterized by abundant synovial infiltration with innate immune cells. Given the role of Toll-like receptors (TLRs) in activation of innate inflammation and the occurrence of TLR-dependent infections after tumor necrosis factor alpha (TNFalpha) blockade treatment, the present study was undertaken to analyze TLRs and their modulation by TNFalpha blockade in SpA.

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from SpA and rheumatoid arthritis (RA) patients during infliximab therapy, and from healthy controls. TLR-2 and TLR-4 expression and TNFalpha production upon lipopolysaccharide (LPS) stimulation were analyzed by flow cytometry on different monocyte subsets. Synovial biopsy specimens from 23 SpA patients before and after infliximab or etanercept treatment, from 15 RA patients, and from 18 osteoarthritis (OA) patients were analyzed by immunohistochemistry.

Results: Expression of TLR-4, but not TLR-2, was increased on PBMCs from patients with SpA, whereas both TLRs were increased in RA patients. TLR expression was particularly increased on the CD163+ macrophage subset. Infliximab reduced TLR-2 and TLR-4 expression on monocytes of SpA and RA patients, leading to lower levels than in controls and to impaired TNFalpha production upon LPS stimulation. In inflamed synovium, the expression of both TLRs and of CD163 was significantly higher in patients with SpA than in those with RA or OA. Paralleling the systemic effect, TLRs in synovium were down-regulated following treatment with infliximab as well as etanercept, indicating a class effect of TNFalpha blockers.

Conclusion: Inflammation in SpA is characterized by increased TLR-2 and TLR-4 expression, which is sharply reduced by TNFalpha blockade. These findings suggest a potential role of innate immunity-mediated inflammation in SpA and provide an additional clue regarding the mechanism of action as well as the potential side effects of TNFalpha blockade.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / therapeutic use*
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Down-Regulation
  • Etanercept
  • Female
  • Flow Cytometry
  • Humans
  • Immunoenzyme Techniques
  • Immunoglobulin G / therapeutic use*
  • Infliximab
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Membrane Glycoproteins / metabolism*
  • Middle Aged
  • Osteoarthritis, Knee / drug therapy
  • Osteoarthritis, Knee / immunology
  • Osteoarthritis, Knee / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Spondylarthropathies / drug therapy*
  • Spondylarthropathies / immunology
  • Spondylarthropathies / metabolism
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Antirheumatic Agents
  • Immunoglobulin G
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, Tumor Necrosis Factor
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Etanercept