Vitamin D attenuates human gingival fibroblast inflammatory cytokine production following advanced glycation end product interaction with receptors for AGE

Background and Objectives Vitamin D [1,25( OH ) 2 D 3 or 1,25D3] is critical in musculoskeletal health, inflammation, immune response, and glucose metabolism. Patients with vitamin D deficiency may be at higher risk of diabetes and periodontitis. Diabetic patients exhibit exacerbated inflammation and more periodontal destruction. Advanced glycation end products ( AGE s), formed during diabetic hyperglycemia, activate inflammatory pathways in periodontitis. Human gingival fibroblasts ( HGF s) express receptors for AGE s ( RAGE s) and can contribute to inflammation. Objectives Determine whether glycated human serum albumin (G‐ HSA ) augments HGF IL ‐6 and IL ‐8 production, and whether treatment with 1,25D3 attenuates cytokine production following stimulation with G‐ HSA + IL ‐1β and/or IL ‐17. Material and Methods HGFs were incubated ±G‐ HSA or normal human serum albumin ( HSA ), ± IL ‐1β and/or IL ‐17, ±1,25D3. Cytokines were measured by ELISA . Neutralizing anti‐ RAGE was used to assess AGE ‐ RAGE interaction. Endotoxin was measured using the ToxinSensor™ System. Data were expressed as mean ± standard deviation and analyzed using a one‐way analysis of variance ( ANOVA ) and Scheffe's F procedure for post hoc comparisons. Results G‐HSA or IL ‐1β, but not HSA , significantly stimulated IL ‐6 and IL ‐8 production. G‐ HSA or HSA when combined with IL ‐1β or IL ‐1β + IL ‐17 synergistically stimulated IL ‐6 and IL ‐8. Neutralizing anti‐ RAGE inhibited IL ‐6 and IL ‐8 produced by cells stimulated with IL ‐1β + G‐ HSA but not (+ HSA ). Synergism caused by HSA did not appear to be mediated by endotoxin since its levels in G‐HSA and HSA were not sufficient to stimulate fibroblasts. Vitamin D inhibited IL‐6 and IL‐8 production stimulated by G‐HSA or HSA + IL‐1β or IL‐1β + IL‐17. Conclusions Results suggest that the “perioprotective” effects of vitamin D are related to its ability to regulate inflammatory cytokine production by HGF s following AGE ‐ RAGE interaction.