High levels of the pro-inflammatory cytokine tumour necrosis factor (TNF) have been associated with many diseases including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Our lab is studying the post-transcriptional regulation of TNF expression. Recently, we have identified the RNase Zc3h12c as a potential repressor of Tnf mRNA expression.
To study the physiological role of Zc3h12c as well as its distribution in vivo, we have engineered a mutant allele in which the green fluorescent protein GFP replaces Zc3h12c. Our aim is to study the consequences of the loss of Zc3h12c on the inflammatory and immune responses.
Zc3h12c-deficient mice are found at the expected Mendelian frequency and look outwardly normal. In particular, they do not present any phenotype related to an excess of TNF expression (like cachexia or arthritis), even at an advanced age.
However, loss of Zc3h12c leads to an absence of structure in secondary lymphoid tissues, and hypertrophic lymph nodes with supernumerary B cells and inflammatory dendritic cells in ageing mice.
Flow-cytometry analysis of our GFP-reporter mouse showed that dendritic cells (DC) are the immune cell type expressing Zc3h12c the most. We found that Zc3h12c-deficient mice have an impaired anti-viral immune response when challenged with LCMV.
To evaluate the potential role of Tnf in this phenotype, we generated mice lacking both Tnf and Zc3h12c. Unexpectedly, 40% of TNF/12c double knock-out mice developed lethal systemic auto-inflammation including pancreatitis, myocarditis, otitis, myositis, pyelonephritis, anaemia, extramedullary haematopoiesis and bone-marrow failure.
These observations are raising new questions on the role of Tnf and Zc3h12c in the control of immune response and inflammation.