PROSTAGLANDIN E2 INDUCES ONCOSTATIN M EXPRESSION IN HUMAN CHRONIC WOUND MACROPHAGES THROUGH AXL RECEPTOR TYROSINE KINASE PATHWAY1

Monocytes and macrophages (mϕ) are plastic cells whose functions are governed by microenvironmental cues. Wound fluid bathing the wound tissue reflects the wound microenvironment. Current literature on wound inflammation is primarily based on the study of blood monocyte-derived mϕ (MDM), cells that have never been exposed to the wound microenvironment. We sought to pair-match compare MDMs with mϕ isolated from chronic wound of patients. Oncostatin M (OSM) was differentially overexpressed in pair-matched wound mϕ. Both PGE 2 and its metabolite 13,14-dihydro-15-keto-PGE 2 (PGE-M) were abundant in wound fluid and induced OSM in wound-site mϕ. Consistently, induction of OSM mRNA was observed in mϕ isolated from PGE 2 –enriched PVA sponges implanted in murine wounds. Treatment of human THP-1 cell-derived mϕ with PGE 2 or PGE-M caused dose-dependent induction of OSM. Characterization of the signal transduction pathways demonstrated the involvement of EP4 receptor and cAMP signaling. In human mϕ, PGE 2 phosphorylated Axl, a receptor tyrosine kinase (RTK). Axl phosphorylation was also induced by a cAMP analog demonstrating interplay between the cAMP and RTK pathways. PGE 2 –dependent Axl phosphorylation led to AP-1 transactivation which is directly implicated in inducible expression of OSM. Treatment of human mϕ or mice excisional wounds with recombinant OSM resulted in an anti-inflammatory response as manifested by attenuated expression of endotoxin-induced TNFα and IL-1β. OSM treatment also improved wound closure during the early inflammatory phase of healing. In summary this work recognizes PGE 2 in the wound-fluid as a potent inducer of mϕ OSM, a cytokine with anti-inflammatory role in cutaneous wound healing.