TLR9, Infectious Disease and Cancer

Mon, 01/14/2013 - 08:22

Toll-like receptor 9 (TLR9) is a protein encoded by TLR9 gene in humans. It is also known as cluster of differentiation 289 (CD289) and is a member of TLR family. Proteins from TLR family are transmembrane proteins that expressed in both antigen-resenting cells (APCs, such as dendritic cells, macrophages and natural killer cells) and non-APCs.  TLRs are located on the cell surface and the endocytic compartment and recognize pathogen-associated molecular patterns (PAMPs), which are specific to infectious pathogens (e.g. viruses, bacteria and fungi). This pattern recognition then leads to signaling pathways that induce the secretion of pro-inflammatory cytokines.

TLR9 specifically recognizes bacterial CpG DNA sequences (CpG-DNA) or synthetic oligodeoxynucleotides containing unmethylated CpG (CpG-ODN) (1). By studying the mechanism of TLR9 activation by CpG-ODN, scientists reported that the nuclear protein high-mobility group box 1 protein (HMGB1) is a key modulator of this activation. HMGB1 is a protein encoded by the HMGB1 gene in human and secreted by activated macrophages and monocytes as a cytokine mediator of inflammation.  HMGB1 interacts and pre-associates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment, and hasten the redistribution of TLR9 to early endosomes in response to CpG-ODN. In addition, HMGB1 accelerates the delivery of CpG-ODN to its receptor, resulting in a TLR9-dependent augmentation of IL6, IL12 and TNFalpha secretion. Loss of HMGB1 can lead to a defect in the cytokine and iNOS response to CpG-ODN.

IF analysis of TLR9 in human plasmacytoid dendritic cells.

TLR9, as well as TLR3, 4 and 7/8 represent promising cancer immunotherapeutics and have been included in the ranked National Cancer Institute’s list with the highest potential to treat cancer (3). CpG 7909 (a TLR9 agonist) has been evaluated in several tumor types, and 10% response rate in patients with metastatic melanoma was observed, along with the evidence of immune activation (4). Also, intralesionally injected CpG showed antitumor activity against basal cell carcinoma and melanoma with both local and systemic immune activation in a Phase I study (5).

Furthermore, CpG-ODNs have been used successfully as adjuvant in cancer vaccines which showed to improve human tumor antigen-specific CD8+ T cell responses (6).  Results from various clinical trials suggest that CpG-ODNs may be used alone or as an adjuvant to immunotherapy to treat conditions such as allergy and asthma (7). Moreover, it has been reported that malaria parasites required TLR9 to activate regulatory T cells for immune escape (8). Activating regulatory T cells is one of the mechanisms by which malaria parasites subvert host immune systems. Malaria vaccines containing TLR9 inhibitors or whole parasites (with adjuvant hemozoin, a malarial heme-detoxification byproduct) have been developed and tested in clinical trials (9).

  1. PMID: 12243247
  2. PMID: 17548579
  3. PMID: 18364014
  4. PMID: 20563267
  5. PMID: 18463532
  6. PMID: 15696196
  7. PMID: 20623989
  8. PMID: 1825045
  9. PMID: 20114028

Novus Biologicals offers TLR9 reagents for your research needs including:


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