**9. Experimental therapies that inhibit activated stat proteins: Is cytokine gene expression altered?**

The results of a Phase 2B RA clinical trial have recently been published which showed that the JAK3-specific SMI, tofacitinib (CP690, 550) had clinical efficacy as measured by the ACR response criteria [218]. However, there has been less progress on developing novel strategies to directly inhibit activated STAT proteins or dampen STAT gene re‐ sponses. Noteworthy have been proof-of-principle studies that activated STAT proteins can be experimentally 'deactivated' which result in the inhibition of STAT/DNA binding. Thus, JNK-mediated phosphorylation of the STAT6 ser707 decreased the DNA binding ca‐ pacity of IL-4-stimulated STAT6 resulting in the inhibition of STAT6-responsive genes [219]. Using immunosuppressive STAT oligodeoxynucleotides (ODN) to inhibit activated STAT proteins have also been relatively successful. These ODN have been shown to in‐ terfere with the phosphorylation of STAT1 and STAT4 [220] and STAT1 and STAT3 [221]. Lastly, administration of a single dose of a STAT1 decoy ODN suppressed joint swelling and the histological appearance of acute and chronic adjuvant-induced experi‐ mental arthritis in the mouse [222]. Electrophoretic mobility shift analysis of the nuclear extracts from synoviocytes from the STAT1 decoy ODN-treated animals incubated with the STAT-1 decoy ODN inhibited STAT-1 binding to DNA. Of note, STAT-1 decoy ODN also inhibited the expression of macrophage CD40 suggesting that interference with CD40-mediated signaling by macrophages may be the mechanism responsible for the at‐ tenuation of arthritis by the STAT-1 decoy ODN.

**Acknowledgments**

**Author details**

Charles J. Malemud\*

**References**

159-168.

65(2) 149-156.

Pathology 2009; 4 417-434.

2011; 2(4) 179-182.

The Arthritis Research Laboratory at Case Western Reserve University School of Medicine was supported by an investigator-initiated project grant from Takeda Pharmaceuticals of North America (Deerfield, IL) and is presently supported by an investigator-initiated project

Suppression of Pro-Inflammatory Cytokines via Targeting of STAT-Responsive Genes

http://dx.doi.org/10.5772/52506

395

Arthritis Research Laboratory, Division of Rheumatic Diseases, Case Western Reserve

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Address all correspondence to: cjm4@cwru.edu

The author declares no conflict of interest.

University School of Medicine, Cleveland, Ohio, USA
