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

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

Author information

1
The Center for Molecular Fetal Therapy, Division of Pediatric, Thoracic and General Surgery, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.

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 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

PMID:
23684616
PMCID:
PMC3759570
DOI:
10.1016/j.jss.2013.04.009
[Indexed for MEDLINE]
Free PMC Article
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