We thank Wang et al.
1 for their instructive comments regarding our manuscript entitled, “Role of miR-146a in the Regulation of Inflammation in an In Vitro Model of Graves' Orbitopathy.”
2 In our study, we found that the level of miR-146a expression was significantly higher in Graves' orbitopathy (GO) adipose tissue compared with non-GO normal controls. Wang et al.
1 questioned the source of the increased miR-146a levels, and cited past reports
3,4 that suggested that peripheral blood CD4+ T cells in the orbital adipose tissue may be one of the sources of the increased levels of miR-146a.
Because microRNA expression is cell- or tissue-specific, we believe further studies are necessary to confirm their hypothesis. In our study, we reported a comparison of the expression levels of miR-146a in GO and non-GO orbital adipose tissues.
2 However, we have also obtained data regarding the expression levels of miR-146a in GO and non-GO orbital fibroblasts. This unpublished data showed that the level of miR-146a expression was higher in GO orbital fibroblasts, compared with non-GO fibroblasts. However, the results did not show whether other cell types, such as orbital adipocyte or CD4+T cells, led to increased miR-146a expression in GO patients. To cite one report not consistent with the hypothesis by Wang et al.,
1 Liu et al.
5 recently reported different miRNA expression in peripheral blood mononuclear cells (PBMCs), consisting of monocytes, T cells, B cells, and other cell types, from 54 Graves' disease (GD) patients and 35 normal controls. The authors reported that changes in levels of miR-154*, miR-374b, and miR-431* were associated with GD, whereas the microarray did not show any significant difference in the miR-146a in PBMCs of GD patients. Although the study did not mention the percentage of GO patients, we believe that some GO patients may have been included in their study.
In addition, Wang et al.
1 suggested a possible role of miR-155 in the regulation of inflammation in GO patients. In previous studies using knockout mice, miR-155 was implicated as a positive regulator of cytokine release from B and T cells.
6,7 Then, several recent studies suggested that miR-155 modulates immunity by regulating the Toll-like receptor/IL-1 inflammatory pathway in a similar manner to miR-146.
8,9 Ceppi et al.
9 reported that miR-155 (and miR-146a) decreased p38 MARK activation and controlled the overproduction of inflammatory cytokines in activated monocyte-derived dendritic cells.
In humans, miR-155 has been reported to be associated with rheumatoid arthritis (RA),
10,11 atherosclerosis,
12 and diabetic nephritis (DN).
13 Huang et al.
13 reported that the expression of both miR-155 and miR-146a increased more than 5-fold in kidney samples of DN patients compared with normal controls. Recently, Li et al.
12 reported that an increased miR-155 level relieves chronic inflammation and plays a protective role by signaling through the miR-155-CARHSP1-TNF-α pathway in atherosclerosis. In a similar manner as miR-146a, miR-155 was found to be upregulated in PBMCs,
11 as well as in synovial fibroblasts and synovial tissue from RA patients.
10 Consistent with these results, most previous studies have reported that both miR-146a and miR-155 were upregulated in inflammatory diseases. We therefore hypothesize that miR-155 plays an important role in the regulation of inflammation in orbital fibroblasts from GO patients, although further studies are needed to confirm the exact role of miR-155 in the regulation of this inflammation.
We appreciate the comments by Wang, Xiao, and Zhang that prompted us to reevaluate an important point that we had not fully considered.
Supported by a grant from the National Research Foundation of Korea (2014R1A1002754); and partially supported by the Soonchunhyang University Research Fund.