Abstract
The human toll like receptor 9 (TLR9) detects differences between microbial and host DNA, based on unmethylated deoxycytidyl deoxyguanosine dinucleotide (CpG) motifs, leading to activation of both innate and adaptive immune mechanisms. The synthetic TLR9 agonist, CpG-ODN, can substitute for microbial DNA in these responses, and is in clinical trials as an immunomodulatory agent in diseases as diverse as infections, cancer and allergic disorders. Human TLR9 is expressed on cells of haematopoietic origin (principally plasmacytoid dendritic cells and B cells), but has also been described as being expressed on a number of other cell types. In order to clarify the expression and function of TLR9 in a range of cells of both haematopoietic and non-haematopoietic origin, we investigated the level of expression of TLR9 mRNA, and the ability of the cells to respond to CpG-ODN by upregulation of cell surface markers, cytokine production, cellular proliferation and activation of NFκB. Our data show that the cellular response to CpG-ODN depended on a threshold level of expression of TLR9. TLR9 was widely expressed amongst B cell tumours (with the exception of myeloma cell lines), but we did not find either threshold levels of expression of TLR9 or responses to CpG-ODN in several myeloma or myeloid tumour cell lines or any non-haematological tumour cell lines tested in our study. TLR9-positive cells varied significantly in their responses to CpG-ODN, and the level of TLR9 expression beyond the threshold did not correlate with the magnitude of the response to CpG-ODN. Finally, CpG-ODN induced NFκB activation and increased cellular proliferation in Hek293 cells that had been stably transfected with hTLR9, but did not affect the expression of surface markers or synthesis of IL-6, IL-10 or TNF-α. Thus both haematological and non-haematological cells expressing appropriate levels of TLR9 respond to CpG-ODN, but the nature of the TLR9-mediated response is dependent on cell type.
Highlights
The immune system has developed defence mechanisms against infectious microorganisms, based on the identification of pathogen associated molecular patterns (PAMPs)
The myeloid lineage cell lines, KG-1 and HL-60 were negative by this criterion (TLR9: -actin ratio
We studied the expression of TLR9 in more than 20 cells and cell lines of both haematological and non-haematological origin, using a semi-quantitative RT-PCR method
Summary
The immune system has developed defence mechanisms against infectious microorganisms, based on the identification of pathogen associated molecular patterns (PAMPs). Crucial to mediating these effects is the family of toll like receptors (TLRs). Studies have reported human TLR9 (hTLR9) expression in other immune cells, such as activated neutrophils, natural killer cells, eosinophils and T lymphocytes [5, 8,9,10]. TLR9 expression has been reported in some non-immune human cell types, such as pulmonary epithelium, keratinocytes and intestinal epithelial cells, and in lung and intestinal tumour cells [11,12,13,14,15]
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