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

J Surg Res. 2013 Sep;184(1):671-7. doi: 10.1016/j.jss.2013.04.009. Epub 2013 Apr 24.


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 same gestation 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.

Keywords: Extracellular matrix; Fetal wound healing; Hyaluronan; IL-10; STAT3.

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Extracellular Matrix / metabolism*
  • Female
  • Fetus / cytology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gestational Age
  • Hyaluronic Acid / biosynthesis
  • Hyaluronic Acid / metabolism*
  • Immunomodulation / physiology
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Interleukin-10 Receptor alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation / physiology
  • Pregnancy
  • STAT3 Transcription Factor / metabolism*
  • Wound Healing / physiology


  • IL10 protein, mouse
  • Interleukin-10 Receptor alpha Subunit
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interleukin-10
  • Hyaluronic Acid