| First Author | Coursey TG | Year | 2016 |
| Journal | Am J Pathol | Volume | 186 |
| Issue | 6 | Pages | 1547-58 |
| PubMed ID | 27085137 | Mgi Jnum | J:233696 |
| Mgi Id | MGI:5787868 | Doi | 10.1016/j.ajpath.2016.02.004 |
| Citation | Coursey TG, et al. (2016) Interferon-gamma-Induced Unfolded Protein Response in Conjunctival Goblet Cells as a Cause of Mucin Deficiency in Sjogren Syndrome. Am J Pathol 186(6):1547-58 |
| abstractText | Goblet cells (GCs) are specialized secretory cells that produce mucins and a variety of other proteins. Significant conjunctival GC loss occurs in both experimental dry eye models and patients with keratoconjunctivitis sicca due to the induction of interferon (IFN)-gamma. With the use of a primary murine culture model, we found that GCs are highly sensitive to IFN-gamma with significantly reduced proliferation and altered structure with low concentrations. GC cultures treated with IFN-gamma have increased gene expression of Muc2 and Muc5AC but do not express these mucin glycoproteins. We hypothesized that IFN-gamma induces endoplasmic reticulum stress and the unfolded protein response (UPR) in GCs. Cultures treated with IFN-gamma increased expression of UPR-associated genes and proteins. Increased GRP78 and sXBP1 expression was found in experimental dry eye and Sjogren syndrome models and was GC specific. Increased GRP78 was also found in the conjunctiva of patients with Sjogren syndrome at the gene and protein levels. Treatment with dexamethasone inhibited expression of UPR-associated genes and increased mucin production. These results indicate that induction of UPR by IFN-gamma is an important cause of GC-associated mucin deficiency observed in aqueous-deficient dry eye. Therapies to block the effects of IFN-gamma on the metabolically active endoplasmic reticulum in these cells might enhance synthesis and secretion of the protective GC mucins on the ocular surface. |
