Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells

Tomohiro Koga, Satoshi Yamasaki, Kiyoshi Migita, Junko Kita, Akitomo Okada, Shinya Kawashiri, Naoki Iwamoto, Mami Tamai, Kazuhiko Arima, Tomoki Origuchi, Hideki Nakamura, Makoto Osaki, Toshiyuki Tsurumoto, Hiroyuki Shindo, Katsumi Eguchi, Atsushi Kawakami
Clinical and Experimental Rheumatology 2011, 29 (6): 906-12

OBJECTIVES: Zc3h12a is an RNA binding protein with a CCCH-type finger motif and is known to regulate mRNA metabolism. Previous reports suggest that Zc3h12a acts as a negative regulator of inflammatory processes because it is involved in the degradation of IL-6 mRNA. We investigate the effect of Zc3h12a on IL-6 production in fibroblast-like synovial cells (FLS) from rheumatoid arthritis (RA) patients.

METHODS: The expression of Zc3h12a in FLS was determined by polymerase chain reaction. To knock down Zc3h12a expression in FLS, siRNA for Zc3h12a was transfected by the lipofection method. The supernatants were collected after siRNA transfection for the quantification of IL-6 production. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was examined by Western blotting. Cell proliferation was analysed by the Cell Counting Kit-8 assay after Zc3h12a knockdown.

RESULTS: mRNA for Zc3h12a were demonstrated in FLS from RA patients. Zc3h12a transcripts were induced by LPS or IL-1β in FLS. The production of IL-6 as well as its mRNA expression was significantly increased by the Zc3h12a knockdown. The Zc3h12a knockdown also induced the activation of STAT3, which the anti IL-6 receptor antibody inhibited. Proliferation of Zc3h12a-knockdown FLS increased significantly in the presence of recombinant soluble IL-6 receptor (sIL-6R).

CONCLUSIONS: Our data suggest that Zc3h12a is a novel IL-6 regulator in FLS, which may be involved in the progression of RA.

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