02461nas a2200385   4500000000100000008004100001260001300042653001000055653002500065653002000090653001100110653001300121653001100134653002700145653001200172653000900184653001600193653002500209653001200234653001800246653003700264653001600301100001400317700001400331700001700345700001300362700001200375700001400387700001200401245011400413300001100527490000700538520151600545022001402061       2013                            d  c2013 Apr10aAdult10aCell Differentiation10aCells, Cultured10aFemale10aFibrosis10aHumans10aInflammation Mediators10aleprosy10aMale10aMiddle Aged10aMycobacterium leprae10aNeurons10aSchwann Cells10aTransforming Growth Factor beta110aYoung Adult1 aPetito RB1 aAmadeu TP1 aPascarelli B1 aJardim M1 aVital R1 aAntunes S1 aSarno E00aTransforming growth factor-β1 may be a key mediator of the fibrogenic properties of neural cells in leprosy.  a351-660 v723 a<p>Fibrosis is the main cause of irreversible nerve damage in leprosy. Phenotypic changes in Mycobacterium leprae (ML)-infected Schwann cells (SCs) have been suggested to mediate this process. We found that SC line cultures stimulated with ML upregulated transforming growth factor-β1 (TGF-β1), and that TGF-β1 or ML induced increased numbers of α-smooth muscle actin (α-SMA)-positive cells with characteristic stress fibers. Mycobacterium leprae and TGF-β1 also induced increased type I collagen and fibronectin mRNA and secretion and augmented mRNA levels of SOX9 and ZEB1, which are involved in the epithelial-mesenchymal transition. These effects could be inhibited by the TGF-β1 type I receptor (ALK5) inhibitor, SB-431542. In nerve biopsies from leprosy-infected patients with varying grades of fibrosis (n = 11), type I and III collagen and fibronectin were found in the endoneurium and perineurium, α-SMA-positive cells filled the fibrotic perineurium but not the endoneurium, and CD34-positive fibroblasts predominated in the endoneurium. Results of transcriptional studies of 3 leprosy nerves and 5 controls were consistent with these data, but α-SMA and other mRNA levels were not different from those in the control samples. Our findings suggest that TGF-β1 may orchestrate events, including reprogramming of the SC phenotype, leading to transdifferentiation, connective tissue cell expansion, and fibrogenesis in the evolution of leprosy nerve lesions during some evolutionary stages.</p>  a1554-6578