A novel role for Tm7sf2 gene in regulating TNFα expression.
We have explored the role of Tm7sf2 gene, which codifies for 3β-hydroxysterol Δ14-reductase, an endoplasmic reticulum resident protein, in the sensitivity to endoplasmic reticulum stress and in the resulting inflammatory response. We used mouse embryonic fibroblasts, derived from Tm7sf2(+/+) and Tm7sf2(-/-) mice, to determine the in vitro effects of thapsigargin on NF-κB activation. Our results show that the Tm7sf2 gene controls the launch of the unfolded protein response and presides an anti-inflammatory loop thus its absence correlates with NF-κB activation and TNFα up-regulation. Our data also show that Tm7sf2 gene regulates liver X receptor activation and its absence inhibits LXR signalling. By expressing the hTm7sf2 gene in KO MEFs and observing a reduced NF-κB activation, we have confirmed that Tm7sf2 gene is linked to NF-κB activation. Finally we used genetically modified mice in an in vivo model of ER stress and of inflammation. Our results show a significant increase in renal TNFα expression after tunicamycin exposure and in the oedematogenic response in Tm7sf2(-/-) mice. In conclusion, we have shown that the Tm7sf2 gene, to date involved only in cholesterol biosynthesis, also controls an anti-inflammatory loop thereby confirming the existence of cross talk between metabolic pathways and inflammatory response.
Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biochimica Cellulare, Università di Perugia, Perugia, Italia. ilaria.bellezza@unipg.it
Ilaria
I
Bellezza
Rita
R
Roberti
Leonardo
L
Gatticchi
Rachele
R
Del Sordo
Maria Grazia
MG
Rambotti
Maria Cristina
MC
Marchetti
Angelo
A
Sidoni
Alba
A
Minelli
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D013312:Stress, Physiological / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
C081452:Atf4 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; D057093:Orphan Nuclear Receptors; D014409:Tumor Necrosis Factor-alpha; D051701:Activating Transcription Factor 4; D002784:Cholesterol; D010088:Oxidoreductases; C022672:delta(14)-sterol reductase