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.
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.
Authors: M T Longaker; D J Whitby; N S Adzick; T M Crombleholme; J C Langer; B W Duncan; S M Bradley; R Stern; M W Ferguson; M R Harrison Journal: J Pediatr Surg Date: 1990-01 Impact factor: 2.545
Authors: N S Adzick; M R Harrison; P L Glick; J H Beckstead; R L Villa; H Scheuenstuhl; W H Goodson Journal: J Pediatr Surg Date: 1985-08 Impact factor: 2.545
Authors: T M Krummel; J M Nelson; R F Diegelmann; W J Lindblad; A M Salzberg; L J Greenfield; I K Cohen Journal: J Pediatr Surg Date: 1987-07 Impact factor: 2.545
Authors: Ben A Croker; Danielle L Krebs; Jian-Guo Zhang; Sam Wormald; Tracy A Willson; Edouard G Stanley; Lorraine Robb; Christopher J Greenhalgh; Irmgard Förster; Björn E Clausen; Nicos A Nicola; Donald Metcalf; Douglas J Hilton; Andrew W Roberts; Warren S Alexander Journal: Nat Immunol Date: 2003-05-18 Impact factor: 25.606
Authors: S Morteza Seyed Jafari; Maziar Shafighi; Helmut Beltraminelli; Benedikt Weber; Ralph A Schmid; Thomas Geiser; Amiq Gazdhar; Robert E Hunger Journal: J Membr Biol Date: 2017-08-03 Impact factor: 1.843
Authors: Alice King; Swathi Balaji; Louis D Le; Timothy M Crombleholme; Sundeep G Keswani Journal: Adv Wound Care (New Rochelle) Date: 2014-04-01 Impact factor: 4.730
Authors: Swathi Balaji; Chad M Moles; Sukanta S Bhattacharya; Maria LeSaint; Yashu Dhamija; Louis D Le; Alice King; Mykia Kidd; Muhammad F Bouso; Aimen Shaaban; Timothy M Crombleholme; Paul Bollyky; Sundeep G Keswani Journal: J Surg Res Date: 2014-02-22 Impact factor: 2.192
Authors: Swathi Balaji; Alice King; Emily Marsh; Maria LeSaint; Sukanta S Bhattacharya; Nathaniel Han; Yashu Dhamija; Rajeev Ranjan; Louis D Le; Paul L Bollyky; Timothy M Crombleholme; Sundeep G Keswani Journal: PLoS One Date: 2015-05-07 Impact factor: 3.240
Authors: Swathi Balaji; Xinyi Wang; Alice King; Louis D Le; Sukanta S Bhattacharya; Chad M Moles; Manish J Butte; Vinicio A de Jesus Perez; Kenneth W Liechty; Thomas N Wight; Timothy M Crombleholme; Paul L Bollyky; Sundeep G Keswani Journal: FASEB J Date: 2016-11-30 Impact factor: 5.191
Authors: R Marisol Herrera-Perez; Sherry L Voytik-Harbin; Jann N Sarkaria; Karen E Pollok; Melissa L Fishel; Jenna L Rickus Journal: PLoS One Date: 2018-03-22 Impact factor: 3.240