# Cytokine Balance in Rheumatoid Arthritis > **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $387,200 ## Abstract An important role for inflammatory cytokines in driving synovial (joint) pathology in rheumatoid arthritis (RA) is well established and has been validated by the success of therapeutic targeting of TNF and IL-6. Inflammatory cytokines drive RA pathogenesis by activating cells in the synovium and inducing recruitment of immune cells. The long term goals of this project are to understand how inflammatory cytokines implicated in RA pathogenesis activate macrophages, an important pathogenic cell type. An associated goal is to identify novel cytokine-mediated pathways that regulate macrophage inflammatory phenotype that can serve as targets for new therapeutic approaches to suppress RA pathogenesis. TNF is a major pathogenic cytokine in RA and a strong activator of inflammatory responses. Classical inflammatory activation of cells by TNF is mediated by canonical NF-B signaling that activates well known TNF target genes such as IL-1 and IL-6. In the previous project period, we used signaling and transcriptomic approaches to investigate novel pathways and gene expression patterns activated by TNF in human macrophages. We found that TNF induced delayed but sustained noncanonical NF-B, Jak and AP-1 signaling that resulted in activation of transcription factors, including STAT3, that are not known to be part of the TNF response. These transcription factors activated expression of late phase TNF-induced genes not currently appreciated to be TNF targets. These genes included feedback inhibitors of inflammatory signaling, and mediators of lipid metabolism that may be important for inflammation-accelerated atherosclerosis. Late phase TNF-induced genes were expressed in RA synovial macrophages, implicating these genes in synovitis. RA synovium is characterized by low oxygen tension (hypoxia) and associated cellular glycolytic metabolism and metabolic stress. The importance of synovial hypoxia in arthritis pathogenesis is becoming increasingly appreciated. We found that hypoxia remodels the late phase TNF response in human macrophages, including attenuation of STAT3-dependent genes and suppression of lipid metabolism genes. Expression of these genes was dependent on the master metabolic regulator mTORC1, and hypoxia downregulated gene expression at least in part by suppressing mTORC1 activity. These results suggest novel mechanisms by which hypoxia and metabolic stress modulate inflammatory responses in RA synovium. Based on our overarching hypothesis that late phase TNF signaling and gene expression, and its regulation by hypoxia and metabolic stress, contribute to RA pathogenesis, we will investigate mechanisms underlying the late phase TNF response, its regulation by hypoxia, and their functional importance for macrophage inflammatory phenotype, arthritis, and inflammation-accelerated atherosclerosis. We anticipate that these studies will reveal new pathways important in the regulation of inflammatory macrophage phenotype, and thus identify new targets f... ## Key facts - **NIH application ID:** 9953979 - **Project number:** 5R01AR050401-15 - **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY - **Principal Investigator:** Lionel B Ivashkiv - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $387,200 - **Award type:** 5 - **Project period:** 2004-09-10 → 2022-01-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9953979 ## Citation > US National Institutes of Health, RePORTER application 9953979, Cytokine Balance in Rheumatoid Arthritis (5R01AR050401-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9953979. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*