Title

 

Authors

V. Alari¹, F. Giordano¹, C. Gotti^2,1, F. Clementi^1,2, D. Fornasari^1,2, R. Benfante^2,1
 
1Dept. of Pharmacology, School of Medicine, University of Milan, Italy; ²CNR- Institute of Neuroscience, Milan, Italy

 

Abstract

The role of the α7 nicotinic acetylcholine receptor (nAChR) subunit in the innate immune system’s inflammatory response was presented only recently¹, being the missing link in the “cholinergic anti-inflammatory pathway”, a process by which acetylcholine from the vagus nerve reduces the release of the pro-inflammatory cytokine TNFα thus allowing for a controlled response to infection¹. The α7 nAChR subunit gene, in humans, is partially duplicated in the genome (CHRFAM7A) with >99% identity from exon 5 to 10 at 1.6 Mb from the classic α7 gene. CHRFAM7A gene is a hybrid of the classic gene (CHRNA7) and of a novel gene (FAM7A), which encodes four novel exons (α7D, α7C,α7B and α7A). This hybrid gene gives rise to two proteins, in the region of 45 kDa, due to alternative start codons, in primary human leukocytes, whose function is currently unknown. The N-terminally portion for each variant, missing part corresponding to exons 1-4, would lack the majority of the neurotransmitter-gated ion-channel ligand binding domain, but the protein products retain the transmembrane region that forms the ion channel. The CHRFAM7A gene seems not to be represented on every chromosome 15, and a polymorphic variant, in linkage disequilibrium with a 2bp deletion in exon 6, in the same orientation to the CHRNA7 gene, has been described in a cohort of patients with bipolar disorders. Using Real Time PCR, we demonstrated exclusive expression of the CHRFAM7A gene subunit in THP-1 monocytic-like cell line, which was down-regulated on treatment with LPS. This reduction in gene expression was mediated by a direct transcriptional mechanism reliant on NF-κB. This effect has been investigated and confirmed in PBL derived primary monocytes and macrophages cell cultures, that express albeit very low levels of the CHRNA7 receptor. Surprisingly, here the conventional α7subunit was up-regulated by LPS treatment, thus suggesting that CHRFAM7A may participate specifically in the innate immune system’s inflammatory response³. These findings suggest that CHRFAM7A down-regulation may be involved in regulating the levels of cell surface α7receptors (a mechanism unique to humans) and the ability of immune cells to respond to acetylcholine released from the vagus nerve during infection. Many recent reports^4-6 have shown that the symptoms of chronic inflammatory disease, such as arthritis, inflammatory bowel disease and ulcerative colitis, can be alleviated by means of treatment with anti-TNFα antibodies or nicotine; however, treatments involving the neutralising of pro-inflammatory cytokines have been found to be inefficacious in the case of acute severe sepsis and toxic shock syndrome, thus indicating the continued need for anti-inflammatory therapies. This and the fact that trials of nicotine therapy have often been characterised by excessive side effects due to a lack of specificity for just one receptor type, underlines the importance of understanding the mechanisms of regulation of α7and its duplicated isoform subunits in response to pro-inflammatory stimuli, to gain further insight into their role in the immune system and the cholinergic anti-inflammatory pathway, and greatly improve the discovery of anti-inflammatory treatments.
 
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6.de Jonge WJ  and Ulloa L (2007) Br J Pharmacol 151, 915-929.