Inhibition of Inflammation due to Advanced Glycation End‐products by Pentoxifylline

Advanced glycation end‐products (AGE) cause activation of protein kinase C (PKC) and therefore increased secretion of the inflammatory cytokine tumor necrosis factor alpha (TNF‐alpha). AGE proteins are formed during the progression of diabetes and normal aging. The objective of our study is to test the ability of phosphodiesterase inhibitors such as pentoxifylline in inhibiting the inflammation due to AGE proteins in cell culture. AGE proteins were prepared under sterile conditions by the reaction of bovine serum albumin with methylglyoxal (MGO‐BSA). TNF‐alpha produced from MGO‐BSA exposed RAW264.7 cells, a monocyte‐macrophage‐like cell line, in the presence and absence of pentoxifylline was measured by performing an immunoassay on the cell culture supernatants. We found that pentoxifylline effectively reduces the TNF‐alpha produced in MGO‐BSA treated cells in a dose‐dependent and time‐dependent manner. Maximum inhibition of TNF‐alpha was found using 0.1 mg/ml pentoxifylline after 12 hours of treatment. We also found that pentoxifylline mediated inhibition of TNF‐alpha production from MGO‐BSA treated cells is regulated by cAMP. cAMP levels in cells treated with MGO‐BSA was found to be decreased in comparison to cells treated with BSA and the levels of cAMP in MGO‐BSA treated cells was restored to control values when the cells were treated with pentoxifylline. These studies indicate a novel role of second messenger molecules such as cAMP in regulating inflammation related to AGE proteins and also open new avenues for treatment of complications associated with AGE proteins in diabetes and normal aging.