Expression and function of Toll-like receptors 2 and 4 in human keratinocytes

Int Immunol. 2003 Jun;15(6):721-30. doi: 10.1093/intimm/dxg068.


Keratinocytes have the ability to kill pathogenic fungi and bacteria by producing antimicrobial substances. Recent studies suggest that microbial components use signaling molecules of the human Toll-like receptor (TLR) family to transduce signals in various cells. Here we provide evidence that keratinocytes express both TLR2 and TLR4 at the mRNA and protein levels, and show that TLR2 and TLR4 are present in the normal human epidermis in vivo and that their expression is regulated by microbial components. The expression of myeloid differentiation protein gene (MyD88), which is involved in the signaling pathway of many TLR, was also demonstrated in keratinocytes. LPS + IFN-gamma increased the expression of TLR2 and TLR4 50- and 5-fold respectively. Treatment of keratinocytes with Candida albicans, mannan, Mycobacterium tuberculosis or LPS with IFN-gamma resulted in the activation and nuclear translocation of NF-kappaB. Inhibition of NF-kappaB blocked the Candida-killing activity of keratinocytes, suggesting that the antimicrobial effect of keratinocytes requires NF-kappaB activation. LPS + IFN-gamma, C. albicans (4 Candida/KC), peptidoglycan (1 micro g/ml) or M. tuberculosis extract significantly increased IL-8 gene expression after 3 h of treatment (P < 0.05). The increases over the 0-h level were 15-, 8-, 10.8- and 7-fold, respectively. The microbial compound-induced increase in IL-8 gene expression could be inhibited by anti-TLR2 and anti-TLR4 neutralizing antibodies, suggesting that TLRs are involved in the pathogen-induced expression of this pro-inflammatory cytokine. Our findings stress the importance of the role of keratinocytes as a component of innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / drug effects
  • Antigens, Differentiation / physiology
  • Candida albicans / immunology
  • Cells, Cultured
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Epidermal Cells
  • Gene Expression Regulation
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Interferon-gamma / pharmacology
  • Interleukin-8 / immunology
  • Keratinocytes / drug effects
  • Keratinocytes / physiology*
  • Lipopolysaccharides / pharmacology
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / physiology*
  • Mycobacterium tuberculosis / immunology
  • Myeloid Differentiation Factor 88
  • NF-kappa B / immunology
  • Peptidoglycan / immunology
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / physiology*
  • Receptors, Immunologic / drug effects
  • Receptors, Immunologic / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Interleukin-8
  • Lipopolysaccharides
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Peptidoglycan
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Interferon-gamma