Cortisol biosynthesis in the human ocular surface innate immune response

• Published in: PloS one Vol. 9; no. 4; p. e94913
• Main Authors: Susarla, Radhika, Liu, Lei, Walker, Elizabeth A, Bujalska, Iwona J, Alsalem, Jawaher, Williams, Geraint P, Sreekantam, Sreekanth, Taylor, Angela E, Tallouzi, Mohammad, Southworth, H Susan, Murray, Philip I, Wallace, Graham R, Rauz, Saaeha
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: 11β-Hydroxysteroid dehydrogenase; Activation; Adolescent; Adrenal Cortex Hormones - biosynthesis; Adult; Aged; Aged, 80 and over; Aqueous Humor - metabolism; Bioavailability; Biology and Life Sciences; Biomarkers; Biosynthesis; Bullous pemphigoid; Carbon tetrachloride; Case-Control Studies; CCL3 protein; CCL4 protein; Chemotaxis; Chromatography; Cornea; Corneal Stroma - drug effects; Corneal Stroma - metabolism; Cortisol; Cortisone; CXCL10 protein; Cytokines; Cytokines - metabolism; Dehydrogenases; Dendritic cells; Diabetes; Endocrinology; Epithelial cells; Epithelium, Corneal - drug effects; Epithelium, Corneal - metabolism; Eye - immunology; Eye - metabolism; Fibroblasts; Genes; Glucocorticoids; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Granulocyte-macrophage colony-stimulating factor; Hormones; Humans; Hydrocortisone; Immune response; Immune system; Immunity, Innate; Immunology; Inflammation; Innate immunity; Interleukin 6; Keratitis; Keratitis - immunology; Keratitis - metabolism; Keratitis - pathology; Kinases; Lipids; Lipopolysaccharides; Macrophage colony-stimulating factor; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Medicine and Health Sciences; Metabolism; Middle Aged; Monocyte chemoattractant protein 1; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; Mucosa; Ophthalmology; Pemphigoid; Physiological aspects; Proteins; Stevens-Johnson syndrome; Tearing; TLR3 protein; Toll-like receptors; Toll-Like Receptors - metabolism; Tumor necrosis factor-α; Young Adult; γ-Interferon; United Kingdom
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094913

Innate immune responses have a critical role in regulating sight-threatening ocular surface (OcS) inflammation. While glucocorticoids (GCs) are frequently used to limit tissue damage, the role of intracrine GC (cortisol) bioavailability via 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in OcS defense, remains unresolved. We found that primary human corneal epithelial cells (PHCEC), fibroblasts (PHKF) and allogeneic macrophages (M1, GM-CSF; M2, M-CSF) were capable of generating cortisol (M1>PHKF>M2>PHCEC) but in corneal cells, this was independent of Toll-like receptor (TLR) activation. While PolyI∶C induced maximal cytokine and chemokine production from both PHCEC (IFNγ, CCL2, CCL3, and (CCL4), IL6, CXCL10, CCL5, TNFα) and PHKF (CCL2, IL-6, CXCL10, CCL5), only PHKF cytokines were inhibited by GCs. Both Poly I∶C and LPS challenged-corneal cells induced M1 chemotaxis (greatest LPS-PHKF (250%), but down-regulated M1 11β-HSD1 activity (30 and 40% respectively). These data were supported by clinical studies demonstrating reduced human tear film cortisol∶cortisone ratios (a biomarker of local 11β-HSD1 activity) in pseudomonas keratitis (1∶2.9) versus healthy controls (1∶1.3; p<0.05). This contrasted with putative TLR3-mediated OcS disease (Stevens-Johnson Syndrome, Mucous membrane pemphigoid) where an increase in cortisol∶cortisone ratio was observed (113.8∶1; p<0.05). In summary, cortisol biosynthesis in human corneal cells is independent of TLR activation and is likely to afford immunoprotection under physiological conditions. Contribution to ocular mucosal innate responses is dependent on the aetiology of immunological challenge.