The ability to suppress macrophage-mediated inflammation in orbital fat stem cells is controlled by miR-671-5p

Lien, Gi-Shih; Liu, Jen-Fang; Chien, Ming-Hsien; Hsu, Wei-Tse; Chang, Tzu-Hao; Ku, Chia-Chi; Ji, Andrea Tung-Qian; Tan, Peng; Hsieh, Ting-Lieh; Lee, Liang-Ming; Ho, Jennifer H

IL-1RA is a naturally occurring cytokine that is responsive to the physiological IL-1 level for neutralizing the action of IL-1α and IL-1β [39] . MSCs release IL-1RA to antagonize IL-1α and to block TNFα release from activated macrophages [21] . TNFα and IL-1 are two critical cytokines initiating a series of inflammatory response in vivo [40] , and IL-RA-expressing MSCs can modulate the inflammatory response in mice with bleomycin-induced lung inflammation and fibrosis [21] . In addition to IL-1RA, sTNFR type I and sTNFR type II are other inhibitory soluble molecules found in body fluid as well as tissues that reduce the toxic effects of TNFα in the body [41] . sTNFR type II is one of the proteolytic shedding soluble extracellular domains of the tumor necrosis factor receptors secreted primarily by mononuclear cells [42] . Administration of TNFα or LPS to human MSCs increases the concentration of sTNFRs in the medium, suggesting that soluble receptors may be part of a negative feedback mechanism to inhibit the biological effects of TNFα [43] . Yagi and colleagues report that the therapeutic effect of an intramuscular injection of human bone marrow-derived MSCs in endotoxemic animals is dependent on the secretion of sTNFR type I [43] . Our previous work demonstrated that systemic OFSC transplantation upregulated serum level of sTNFR type II, not sTNFR type I, in the first 6 hours after intratracheal injection of LPS [23] . In this study, we demonstrated that both IL-1RA and sTNFR type II expressions in OFSCs were consequences in response to IL-1 and TNFα secretion by LPS-activated macrophages ( Figure 4D,E) .