Background: Antibodies (Abs) to K-Α1-tubulin (KΑ1T), an epithelial gap junction cytoskeletal protein, and Interleukin (IL)-17, have been implicated in the pathogenesis of bronchiolitis obliterans syndrome (BOS) following human lung transplantation (LTx). In this study, we investigated the ability of anti-KΑ1T and IL-17 to induce pro fibrotic periostin and their role in the pathogenesis of BOS following LTx.
Materials and Methods: Broncho alveolar lavage (BAL) from 7 BOS(+) and 7 BOS(-) LTx recipients was analyzed. Normal human primary bronchial epithelial (NHBE) cells were cultured in vitro. Computational promoter sequence analysis of the Periostin promoter was performed to define putative binding sites for transcription factors. Transcription factors were analyzed by immunoprecipitation, chromatin (Ch)-IP and Western blot. Growth factor determination was done by RT-PCR, Western blot, fluorescence microscopy and fibroblast proliferation assays.
Results: Cells isolated from BAL demonstrated increased expression of Periostin gene (>4 fold) in BOS(+) LTx in comparison to BOS(-) LTx. In vitro stimulation of NHBE cells either by KΑ1T Abs or IL-17 demonstrated a 4.3 fold increases in periostin protein expression. However, combination of KΑ1T Abs and IL-17 demonstrated a 16.8 fold increase in periostin. Periostin promoter analysis and specific siRNA knock-down revealed that KΑ1T Abs induces periostin through cJNK, while IL-17 induced periostin via STAT3. Fibroblast proliferation induced by the supernatant collected from NHBE cells stimulated by KΑ1T Abs and IL-17 also demonstrated increased expression of collagen I (>9.1 fold) indicative of a direct fibrogeneic role of KΑ1T Abs and IL-17.
Conclusion: Abs to KΑ1T and IL-17 induced fibrogenesis through cJNK and STAT3 mediated upregulation of pro-fibrotic biomarker, periostin. We propose that this may facilitate the development of BOS following LTx. Therefore, periostin can serve as a novel biomarker in early identification of LTx at risk for development of BOS.
To cite this abstract in AMA style:Tiriveedhi V, Sarma N, Hachem R, Trulock E, Patterson G, Mohanakumar T. Antibodies to K-α1 Tubulin and IL 17 Induces Periostin Dependent Pro-Fibrotic Signaling Cascades: A Novel Biomarker Involved in the Pathogenesis of Chronic Lung Allograft Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/antibodies-to-k-1-tubulin-and-il-17-induces-periostin-dependent-pro-fibrotic-signaling-cascades-a-novel-biomarker-involved-in-the-pathogenesis-of-chronic-lung-allograft-rejection/. Accessed June 13, 2021.
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