ABSTRACT
Tumour necrosis factor alpha (TNF)-α-induced adipose-related protein (TIARP) is a negative regulator of inflammation in arthritis model mice. In humans, six-transmembrane epithelial antigen of prostate 4 (STEAP4) (human counterpart of TIARP) is also expressed in CD14+ monocytes from patients with rheumatoid arthritis (RA). Recently, highly levels of exon 3-spliced variant STEAP4 (v-STEAP4) expression have been observed in porcine lung. The aim of this study is to elucidate the expression and functional role of v-STEAP4, comparing it with that of STEAP4, in the pathogenesis of arthritis. We identified v-STEAP4 in CD14+ cells. The expression of STEAP4 and v-STEAP4 was higher in patients with RA than in healthy participants. We also found that STEAP4 and v-STEAP4 were correlated positively with C-reactive protein and that their expression was decreased after treatment with an interleukin (IL)-6 antagonist in patients with RA. To investigate further the role of STEAP4 and v-STEAP4, we produced STEAP4 and v-STEAP4 over-expressing human monocytic cell lines (THP-1) for functional analysis. In the v-STEAP4 over-expressing cells, the production of IL-6 was suppressed significantly, but TNF-α was increased significantly through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p-)nuclear factor kappa B (NF-κB) was increased after LPS stimulation and degradation of nuclear factor kappa B inhibitor alpha (IκBα) was sustained, whereas p-signal transducer and activator of transcription 3 (STAT-3) was decreased with v-STEAP4. We identified specific up-regulation of v-STEAP4 in RA monocytes. V-STEAP4 might play a crucial role in the production of TNF-α and IL-6 through NF-κB and STAT-3 pathways, resulting in the generation of RA.
Subject(s)
Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/metabolism , Membrane Proteins/metabolism , Monocytes/immunology , Oxidoreductases/metabolism , RNA Isoforms/metabolism , Animals , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Humans , Interleukin-6/metabolism , Lipopolysaccharide Receptors/metabolism , Lipopolysaccharides/immunology , Membrane Proteins/genetics , Mice , NF-kappa B/metabolism , Oxidoreductases/genetics , RNA Isoforms/genetics , RNA Splicing , STAT3 Transcription Factor/metabolism , Signal Transduction , Swine , THP-1 Cells , Tumor Necrosis Factor-alphaABSTRACT
OBJECTIVE: The objective of this paper is to identify predictors for the response to treatment of acute lupus hemophagocytic syndrome (ALHS). METHODS: We reviewed seven cases with ALHS admitted to our hospital and published ALHS cases identified in the 2001-2014 Medline database, and then conducted univariate and multivariate analyses to identify predictors for the response to treatment. RESULTS: Review of our cases showed a significant and negative correlation between serum ferritin and anti-DNA antibody (p = 0.0025). All three patients treated with cyclosporine A (CsA) were considered responders despite high serum ferritin and corticosteroid resistance. We also reviewed 93 patients with ALHS identified in 46 articles. Multiple logistic regression analysis identified C-reactive protein (CRP) (OR 0.83, p = 0.042) and hemoglobin (OR 1.53, p = 0.026) measured at diagnosis of ALHS as significant predictors of the response to corticosteroid monotherapy. Moreover, among 32 patients treated with CsA, serum ferritin was significantly higher in CsA responders (12163 ± 16864 µg/l, n = 22) than in non-responders (3456 ± 6267/µg/l, p = 0.020, n = 10). Leukocyte count was significantly lower in the CsA responders (1940.0 ± 972.3/µl) than in the non-responders (3253 ± 2198/µl, p = 0.034). CONCLUSION: Low CRP and high hemoglobin can predict a positive response to corticosteroid monotherapy while high serum ferritin and low leukocyte count can predict a positive response to CsA in patients with ALHS and therefore, when corticosteroid monotherapy is not effective in such cases, CsA could be the first choice of an additional immunosuppressive agent.