Interleukin-10 regulates the fetal hyaluronan-rich extracellular matrix via a STAT3-dependent mechanism

Alice King, Swathi Balaji, Emily Marsh, Louis D. Le, Aimen F. Shaaban, Timothy M. Crombleholme, Sundeep G. Keswani*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Background: The midgestational fetus is capable of regenerative healing. We have recently demonstrated a novel role for the anti-inflammatory cytokine interleukin 10 (IL-10) as a regulator of hyaluronan (HA) in the extracellular matrix. The signaling pathway of IL-10 has been studied in monocytes but is unknown in dermal fibroblasts. We hypothesized IL- 10 signals through its primary receptor, IL-10R1, to activate STAT3, resulting in HA synthesis. Methods: Murine midgestational (E14.5) fetal fibroblasts were evaluated in vitro. Pericellular matrix was quantified using a particle exclusion assay. STAT3 levels and cellular localization were evaluated by Western blot/band densitometry and immunocytochemistry/confocal microscopy. HA levels were quantified by enzyme-linked immunosorbent assay. The effects of IL-10R1 signal blockade by a neutralizing antibody and STAT3 inhibition were evaluated. An ex vivo midgestation fetal forearm culture incisional wound model in control and transgenic IL-10-/- mice was used to evaluate the role of STAT3 on the extracellular matrix. Results: Fetal fibroblasts produce a robust hyaluronan-rich pericellular matrix that is IL-10R1 and STAT3 dependent. Inhibition of IL-10R1 signaling results in decreased phosphorylated STAT3 levels and inhibition of nuclear localization. Inhibition of STAT3 results in decreased HA production. At day 3, midgestation fetal wounds have efficient re-epithelialization, which is significantly slowed in IL-10-/- wounds at the samegestation and with inhibition of STAT3. Conclusions: Our data demonstrate that IL-10 regulates HA synthesis through its primary receptor IL-10R1 and STAT3 activation. This supports a novel nonimmunoregulatory mechanism of IL-10 in its role in fetal regenerative wound healing.

Original languageEnglish (US)
Pages (from-to)671-677
Number of pages7
JournalJournal of Surgical Research
Volume184
Issue number1
DOIs
StatePublished - 2013

Keywords

  • Extracellular matrix
  • Fetal wound healing
  • Hyaluronan
  • IL-10
  • STAT3

ASJC Scopus subject areas

  • Surgery

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