Conclusions The present study collectively suggests RO9021 is a selective, potent and orally bioavailable small molecule SYK kinase in hibitor, which could serve as a promising chemical lead for the design of clinical SYK inhibitors and could complement the current arsenal of tools in development for treatment of inflammation related and autoimmune related disorders. Introduction Rheumatoid arthritis is characterized by chronic inflammation, articular destruction and abnormal immune response. Although the pathogenesis of RA remains unclear, the accumulated evidence has sug gested that cytokines play an important role in the development and maintenance of RA disease activity. In the past decade, numerous studies have shown that a variety of cytokines including TNF a, IL 1a, 1b, 6, 7, 15, 17, 18, 21, 23, 32, and 33 contribute to RA pathogenesis.

Consequently, biologics that target TNF a or IL 6 for the treatment of RA have been extensively studied and have profoundly changed RA treatment strategy. Considering about 30% of RA patients could experience an inadequate response to current biologics, it is still a challenge to identify key cytokines involved in RA. Recently, the upregulation of interferon inducible genes has been found in the syno vial lining regions and whole blood of patients with RA, suggesting that interferons may also play an important role in the pathogenesis of RA. The classical interferon family cytokines are known to be critically involved in both innate and adaptive immune responses during viral infection and autoimmune inflammation.

The IFN family includes three subfamilies. Type I IFNs include IFN a, b, , ��, , ��, and �� subtypes, whereas type II IFNs are represented by IFN g. Type III IFNs consist of three newly identified members, IL 29, IL 28A and IL 28B. Type III IFNs closely resemble the type I IFNs in terms of expression after virus infection as well as intracellular signaling and activation of antiviral host factors in sus ceptible cells. However, the striking differences between type I and III IFNs include the cell type and tissue specific distribution of their respective receptor complexes. Type I IFNs signal through a universally expressed cell surface receptor complex composed of two subunits, IFNAR1 AV-951 and IFNAR2. By contrast, type III IFNs act through a cell surface receptor com posed of a unique IL 28 receptor a chain and IL 10R2 chain that is also the subunit of the receptor of IL 10, IL 22 and IL 26. The specific activity of type III IFNs is determined in part by the expression level of its receptor chain IL 28Ra, which is expressed on a limited range of tissues and cell types, such as lung, heart, liver and prostate tis sues, dendritic cells, A549 and HeLa S3 cell lines.