Abstract
We report an inverse relationship between expression of the orphan candidate tumor suppressor gene esophageal cancer related gene 4 (Ecrg4), and the mucosal epithelial cell response to infection in the middle ear (ME). First, we found constitutive Ecrg4 mRNA expression in normal, quiescent ME mucosa that was confirmed by immunostainning of mucosal epithelial cells and immunoblotting of tissue lysates for the 14 kDa Ecrg4 protein. Upon experimental ME infection, Ecrg4 gene expression rapidly decreased by over 80%, between 3 to 48 hrs, post infection. When explants of this infected mucosa were placed in culture and transduced with an adenovirus (AD) encoding Ecrg4 gene (ADEcrg4), the proliferative and migratory responses of mucosal cells were significantly inhibited. ADEcrg4 transduction of control explants from uninfected MEs had no effect on basal growth and migration. Over-expression of Ecrg4 in vivo, by pre-injecting MEs with ADEcrg4 48 hrs prior to infection, prevented the natural down-regulation of Ecrg4, reduced mucosal proliferation and prevented inflammatory cell infiltration normally observed after infection. Taken together, these data support a hypothesis that Ecrg4 plays a role in coordinating the inflammatory and proliferative response to infection of mucosal epithelium suggesting a possible mechanism for its putative anti-tumor activity.
Highlights
Mucosal surfaces represent a major barrier lining and protecting the ducts of the eye, ear, exocrine glands and the aero-digestive and uro-genital tracts [1]
We showed that while esophageal cancer related gene 4 (Ecrg4) is constitutively expressed in normal epithelial mucosa, it is rapidly down-regulated during bacterially mediated otitis media (OM) and that with its inappropriate expression during infection, it can modulate the natural course of the inflammatory response both in vitro and in vivo
We found that Ecrg4 is constitutively localized to the normal mucosa but that unlike may other genes, Ecrg4 gene expression is rapidly down-regulated after infection
Summary
Mucosal surfaces represent a major barrier lining and protecting the ducts of the eye, ear, exocrine glands and the aero-digestive and uro-genital tracts [1]. Mucosal epithelia serve critical homeostatic functions as biological, physical and mechanical barriers that regulate innate and adaptive immunities and the tissue response to infection and injury [2,3]. The identification of paracrine, juxtacrine and autocrine factors that control the inflammatory response has led to significant refinements in our understanding of tissue homeostasis. Local factors that are constitutively produced in tissues respond to changes in the local milieu to play critical roles in defining ultimate biological responses. The induction of alarmin genes [11,12] after inflammation is a response to the detection of biological, chemical and physical threats that disrupt tissue homeostasis
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