Small proline-rich proteins 2 are noncoordinately upregulated by IL-6/STAT3 signaling after bile duct ligation

Abstract

Small proline-rich proteins 2 (SPRR2) are coordinately expressed with other epidermal differential complex (EDC) genes in the skin. They function as crosslinking proteins that form bridges between other proteins that comprise the cornified cell envelope, which is the major barrier against the environment. IL-6 is invariably produced at sites of biliary tract injury and IL-6-deficient (IL-6 À/À ) mice show impaired barrier function after bile duct ligation (BDL). Screening microarray analysis identified noncoordinate expression of SPRR2 as a candidate gene that is: (a) expressed in biliary epithelial cells (BEC); (b) IL-6 responsive; and (c) potentially related to biliary barrier function. Therefore, we studied in detail the regulation of BEC SPRR2A expression, in vitro; and tested the hypothesis that if BEC SPRR2 expression contributes to biliary barrier function, it should be increased after BDL in IL-6-wild type (IL-6 þ / þ ) mice and not in IL-6 À/À mice. In vitro studies confirmed that IL-6/gp130-signaling, mediated primarily by signal transducer and activator of transcription 3 (STAT3), stimulated noncoordinate BEC SPRR2 expression. In vivo, noncoordinate upregulation of BEC SPRR2 expression after BDL was seen in the IL-6 þ / þ mice and was unrelated to squamous metaplasia. IL-6 À/À mice showed deficient BEC SPRR2 expression after BDL associated with impaired barrier function, as evidenced by smaller diameters of obstructed ducts, decreased bile volume, and an inability to form 'white bile' compared to IL-6 þ / þ mice at 12 weeks after BDL. IL-6 replacement therapy reversed the barrier defect in IL-6 À/À mice after BDL, coincident with recovery of SPRR2A expression. SPRR2 in diseased mouse and human liver localized subjacent to the apical plasma membrane of BEC lining bile ducts, but was more diffusely expressed throughout the cytoplasm of cholangioles. In conclusion, BEC IL-6/gp130/STAT3 signaling noncoordinately upregulates BEC SPRR2 that appears to contribute to modification of the biliary barrier under conditions of stress.

Epidermal barrier formation and recovery in skin disorders

“…Similarly, Sprr genes are strongly upregulated in intestinal epithelium both in response to bacterial colonization and with induction of allergic gastrointestinal inflammation (62,63). Duct ligation results in SPRR gene induction in biliary epithelial cells related to recovery of barrier function (64). These results suggest that there is a common stress response within epidermal, intestinal, bronchial, and biliary epithelium in response to infection.…”

Gene expression pattern and hormonal regulation of Small Proline-Rich Protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy

“…Evidence has shown that SPRR2 proteins participate in the response to various stresses in many tissues without a stratified epithelium. In the biliary tract, the expression of SPRR2 members is highly induced under stress injury [29]. Similarly, SPRR1A and SPRR2A are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress, and these proteins could protect cardiomyocytes against ischemic injury [30].…”

Liver regeneration

“…IL6 is not a direct mitogen for hepatocytes and does not enhance the mitogenic effect of other growth factors. It is, however, a direct mitogen for biliary cells (Liu et al, 1998) and it has important effects on integrity of the intrahepatic biliary tree by regulating production of small proline-rich proteins by cholangiocytes (Nozaki et al, 2005;Demetris et al, 2006). IL6 does increase in plasma following PHx.…”