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- Title
A160: Role of Interleukin-1 in Abnormal Monocyte Phenotype in Systemic Onset Juvenile Idiopathic Arthritis.
- Authors
Zhang, Yujuan; Macaubas, Claudia; Gupta, Saloni; Klein, Clarissa; Pascual, Virginia; Hay, Arielle; Thompson, Susan D.; Sandborg, Christy I.; Ilowite, Norman T.; Mellins, Elizabeth D.
- Abstract
Background/Purpose: Monocytes phenotype changes in different microenvironments: the proinflammatory M1, regulatory M2, and M2-like phenotypes are each regulated by specific transcriptional factors (TFs). We have observed altered phenotypes in blood monocytes in systemic onset juvenile idiopathic arthritis (sJIA), including a decreased M1 cells, an increased mixed M1/M2 cells, and reduced secretion of IL-1, despite an increased IL-1b response to LPS (PMID 22281427). Here, we investigate whether these monocyte phenotypes are affected by IL-1 blockade. We analyzed monocytes from RAPPORT ( RAndomized Placebo Phase study Of Rilonacept in the Treatment of sJIA) patients to determine levels of TFs involved in monocyte polarization and expression of genes related to IL-1 secretion, before and after treatment with Rilonacept, an IL-1 trap. Methods: Subjects on the Rilonacept arm received active drug from week 0 for a total of 24 weeks; subjects on the placebo arm received placebo for 4 weeks, then Rilonacept for 20 weeks. Blood samples were obtained at week 0, 2, 4, 14 and 24. We used real time PCR to measure M1 associated genes: Interferon Regulatory factor (IRF) family IRF5, STAT1; M2 associated genes IRF4, STAT6, Kruppel-Like Factor 4 (KLF4) and peroxisome proliferator-activated receptor-γ (PPAR-γ); IL-1 secretion related genes: RAB39, RAB27A, RAB27B, P2RX7, and IL-1β. All TFs levels were normalized by the average levels of 3 housekeeping genes. Results: 30 non-paired RNA samples from 15 subjects were tested. Samples from subjects treated with Rilonacept for ≥10 weeks (Late RAPPORT) showed decreased expression of M2 genes, especially KLF4, compared to those untreated or treated for <10 weeks (Early RAPPORT) (Fig ), except for PPAR-γ. Samples collected when there was clinical improvement also showed reduced KLF4 (Fig .). The expression of TFs following IL-1 inhibition in sJIA patients is distinct from normal controls. Levels of IL-1 secretion related genes, except for RAB27B, also were reduced in 'Late RAPPORT' samples (Fig .).
- Subjects
MONOCYTES; INTERLEUKINS; JUVENILE idiopathic arthritis; PHENOTYPES; RANDOMIZED controlled trials; PHYSIOLOGY
- Publication
Arthritis & Rheumatology, 2014, Vol 66, pS207
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.38586