Deficient Expression of PTPN2 Contributes to JAK/STAT3 Hyperactivation in Juvenile Dermatomyositis via Impaired Negative Regulation

Objective Interleukin-6/janus kinase/signal transducer and activator of transcription 3 (IL-6/JAK/STAT3) signaling pathway was abnormally activated in patients with juvenile dermatomyositis (JDM). This study aimed to elucidate the negative regulation mechanisms of JAK/STAT3 signaling pathway in the pathogenesis of JDM. Methods Primary human skeletal muscle cells (HSMCs) were isolated from treatment naive JDM and controls. Transcription levels of negatively regulated genes of STAT3 were screened by quantitative real time polymerase chain reaction (qPCR). Based on the above results, protein tyrosine phosphatase non-receptor type 2 ( PTPN2 ) was selected as the target gene for the following experiments. Western blot analysis of T cell protein tyrosine phosphatase (TC-PTP) was conducted in the biopsy samples of JDM and controls. Phosphorylation level of STAT3 in HSMCs knocked down of PTPN2 (HSMCs PTPN2 -) or over-expression of PTPN2 (HSMCs PTPN2 +) were tested. Results In the major negative regulatory genes of STAT3, suppressors of cytokine signaling ( SOCS ) 2 and SOCS3 were increased. SOCS4 and protein tyrosine phosphatase ( PTPN1, PTPN2, SHP1, SHP2, PIAS1, PIAS2 , and PTPRD ) were decreased in JDM. PTPN2 transcriptional levels exhibited the most pronounced and stable decline in primary skeletal muscle cells derived from JDM patients. TC-PTP was observed deficient expression in the muscle tissues of JDM. Over-expression of PTPN2 in HSMCs leads to declined phosphorylation of STAT3, both in the cytoplasm and within the mitochondria. PTPN2 deficiency indirectly upregulated SLN transcription in primary JDM myocytes. Conclusion PTPN2 plays an important role in the regulation of phosphorylation of STAT3 in HSMCs. Deficient expression of PTPN2 may lead to over-activation of JAK/STAT3 signaling pathway, both in the cytoplasm and within the mitochondria, with dysregulation of the calcium-regulatory protein SLN.