SHP-1/ Src Complex is a Master Regulator of the IL-12/IL-23 pro- and IL-10/IL-27 Anti-inflammatory Axis in TLR4-activated Signaling Pathways in Human Monocytes and Macrophages

• Main Author: Konarski, Yulia
• Other Authors: Kumar, Ashok
• Language: en
• Published: Université d'Ottawa / University of Ottawa 2013
• Subjects: Immunology; SHP-1; Src; IL-12 family; IL-10; Autoimmune Diseases
• Online Access: http://hdl.handle.net/10393/25999; http://dx.doi.org/10.20381/ruor-3180

Although the etiology surrounding many autoimmune diseases remains unknown, the underlying characteristic of many of these diseases is a disruption in the balance of pro- and anti- inflammatory cytokines It is well established that the dysregulation of the IL-12 family of cytokines, an increase in IL-12/IL-23 and a decrease in IL-27 production has been implicated in these conditions. We used ELISA, RT-PCR, Immunofluorescence and Western immunoblotting in conjunction with pharmalogical inhibitors and siRNA to demonstrate the role of SHP-1/Src in the regulation of IL-12, IL-23, IL-27 and IL-10 in LPS-stimulated human THP-1 cells, monocytes and MDMs. My results show for the first time that Src kinase activity relies on SHP-1 activity, and together this complex functions in TLR4-mediated MyD88 and TRIF pathways. Furthermore Src exhibits a dual role as a positive regulator for anti-inflammatory IL-10/IL-27 and as a negative regulator of pro-inflammatory IL-12/IL-23 downstream of TLR4. Moreover, the involvement of PI3K and JNK MAPK, dependent on SHP-1/Src complex, in the regulation of IL-12 family and IL-10 downstream of TLR4 was shown.