Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an “on-demand” drug delivery system to modulate inflammation

Tzuhua Lin, Jukka Pajarinen, Akira Nabeshima, Laura Lu, Karthik Nathan, Zhenyu Yao, Stuart B. Goodman

研究成果: ジャーナルへの寄稿学術誌査読

35 被引用数 (Scopus)

抄録

Chronic inflammation is associated with up-regulation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and excessive inflammatory cytokine secretion by M1 macrophages. The anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory and tissue-regenerative M2 phenotype, thus reducing inflammation and enhancing tissue regeneration. We have generated NF-κB responsive, or constitutively active IL-4 expression lentiviral vectors transduced into murine bone marrow–derived mesenchymal stromal cells (MSCs). MSCs with a constitutively active IL-4 expression vector produced large quantities of IL-4 continuously, whereas IL-4 secretion was significantly induced by lipopolysaccharide (LPS) in the NF-κB sensing MSCs. In contrast, LPS had no effect on MSCs with IL-4 secretion driven by a constitutively active promoter. We also found that intermittent and continuous LPS treatment displayed distinct NF-κB activation profiles, and this regulation was independent of IL-4 signaling. The supernatant containing IL-4 from the LPS-treated MSCs suppressed M1 marker (inducible nitric oxide synthase [iNOS] and tumor necrosis factor alpha [TNFα]) expression and enhanced M2 marker (Arginase 1, CD206 and IL1 receptor antagonist [IL1Ra]) expression in primary murine macrophages. The IL-4 secretion at the basal, non-LPS induced level was sufficient to suppress TNFα and enhance Arginase 1 at a lower level, but had no significant effects on iNOS, CD206 and IL1Ra expression. Finally, IL-4 secretion at basal or LPS-induced levels significantly suppressed osteogenic differentiation of MSCs. Our findings suggest that the IL-4 secreting MSCs driven by NF-κB sensing or constitutive active promoter have great potential for mitigating the effects of chronic inflammation and promoting earlier tissue regeneration.

本文言語英語
ページ(範囲)1025-1034
ページ数10
ジャーナルCytotherapy
19
9
DOI
出版ステータス出版済み - 9月 2017
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学
  • 腫瘍学
  • 遺伝学(臨床)
  • 細胞生物学
  • 癌研究
  • 移植

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