The early synthesis of p35 and activation of CDK5 in LPS-stimulated macrophages suppresses interleukin-10 production

Abstract

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine that is produced primarily by macrophages. We investigated mechanisms by which the timing of IL-10 production was controlled in macrophages and found that cyclin-dependent kinase 5 (CDK5) activity was markedly increased in lipopolysaccharide (LPS)-stimulated macrophages through the synthesis of the CDK5-binding partner and activator p35. Degradation of p35 released the inhibition on anti-inflammatory signaling mediated by CDK5-p35 complexes. The transiently active CDK5-p35 complexes limited the LPS-stimulated phosphorylation and activation of various mitogen-activated protein kinases (MAPKs), thereby preventing the premature production of SOCS3 (suppressor of cytokine signaling 3), an inhibitor of inflammatory responses in macrophages, and IL-10. Furthermore, we showed that dextran sodium sulfate failed to induce colitis in p35-deficient mice, which was associated with the enhanced production of IL-10 by macrophages. Together, our results suggest that CDK5 enhances the inflammatory function of macrophages by inhibiting the MAPK-dependent production of IL-10.

Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells

“…Given the presence of an AP-1 consensus motif in Il10 and the evidence that potentiation of MAP kinase signaling can increase IL-10 production 1,10,11 , we hypothesized that an increase in AP-1 activity resulting from reduced c-Jun Ser243 phosphorylation may mediate activation of IL-10 following CDK8 inhibition. Supporting this theory, we found that co-treatment of BMDCs with dCA and T-5224 (8), a small-molecule inhibitor of AP-1 reported to bind c-Fos and inhibit its dimerization with c-Jun 32 (Supplementary Fig.…”

“…Alternatively, amplification of mitogen-activated-protein (MAP) kinase signaling by perturbation of microtubule dynamics or inhibition of cyclin-dependent kinase 5 (CDK5) can also upregulate IL-10 (refs. 10,11 ). Notably, these probes have identified therapeutically useful drug targets, exemplified by approval of the PDE4 inhibitor apremilast for treatment of psoriatic arthritis as well as preclinical evaluation for treatment of IBD 12,13 .…”

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…Specifically, Cdk5 activity enhances the inflammatory function of macrophage by regulating MAPK-dependent production of suppressor of cytokine signaling-3 and IL-10. 74 Although experiments mixing BM from Cdk5 2/2C donors with Cdk5 1/1C T cells resulted in a modest improvement in survival after allo-HCT (33% vs 13%, Table 1), systemic GVHD as measured by clinical score was not different between groups underscoring the predominant role of Cdk5 activity in the T-cell compartment as a determinant of GVHD severity. In summary, the accumulating evidence regarding Cdk5-dependent T-cell function has important implications for a broad spectrum of immune and inflammatory disorders.…”

Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish

“…Unlike other members of the cyclindependent kinase family, Cdk5 is activated by the non-cyclin cofactor Cdk5 regulatory subunit 1 (Cdk5r1; also known as p35) (Chae et al, 1997) and is not involved in cell cycle regulation (Dhavan and Tsai, 2001;Lalioti et al, 2010). While Cdk5 has been intensively studied in the context of neural development, several studies have begun to hint at an important role outside the nervous system (Dhavan and Tsai, 2001;Na et al, 2015;Wei et al, 2005). However, the function of Cdk5 in liver development, particularly in biliary network development, has not been studied and there is no evidence yet linking Cdk5 to the pathology of biliary atresia.…”