[Introduction and Objective] Inflammation amplifier (IA), a local chemokine inducer in non-immune cells is induced by simultaneous activation of NFκB and STATs (IL-17, TNFα, and IL-6) and leads to a synergistic production of chemokines, growth factors, and cytokines. IA was essential for the development of inflammation in various disease models including allogeneic lung transplantation. (J Immunol. 189, 1928 and Int. Immunol. 25, 319). The status of IA can be a new biomarker and its regulator can be a new therapeutic target in rejected kidney allografts (KA). The objective of this study was to investigate the contribution of IA during the rejection process in KA and to identify genes regulating IA. [Materials and Methods] Primary human kidney cells (PHKC) were stimulated with IL-17, IL-6, and TNFα, and expressions of chemokines and IL-6 were measured by RT-PCR. Among the genes highly expressed in PHKC with IA activation, we selected a gene named Renal NFkB Enhancer-1 (RNE1) and evaluated the expression of the gene in this model. In another experiment, urinary RNE1 in kidney transplant recipients (KTR) were measured by ELISA and clinical data (serum Cre, CRP, urinary protein, urinary albumin, urinary NAG, and eGFR) were also compared among the KTR patient groups with normal histology, interstitial fibrosis and tubular atrophy (IF/TA), or chronic active antibody-mediated rejection (CAAMR). [Results] PHKC expressed excess amounts of chemokines and IL-6 after IA activation by IL-17, IL-6, and TNFα. Deficiency of RNE1 by siRNA suppressed inflammatory chemokines and IL-6 after IA activation in PHKC, suggesting that RNE1 is a positive regulator in IA. Urinary RNE1 in KTR showed significantly higher amount in CAAMR patients (60955 ng/mgCre, n=9) compared to IF/TA (9417 ng/mgCre, n=26) and normal (5602 ng/mgCre, n=16). In contrast, serum Cre, eGFR, U-NAG levels showed no significant difference among the patient groups. [Conclusion] IA was activated in PHKC, and urinary RNE1 was elevated in KA with CAAMR. These results suggested that activation of IA is involved in development of CAAMR, and RNE1 could be a new biomarker for the diagnosis. Now, we are planning to examine detailed molecular mechanisms how RNE1 regulates NF-kB pathway in KA and to examine if it will be a new therapeutic target for CAAMR.

CITATION INFORMATION: Higuchi H, Iwami D, Hotta K, Shinohara N, Murakami M. Activation of Inflammation Amplifier in Kidney Graft and Urinary Biomarker for Chronic Rejection. Am J Transplant. 2017;17 (suppl 3).

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