p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

Abstract

Induction of cyclin-dependent kinase (CDK) inhibitor gene p16INK4a into the synovial tissues suppresses rheumatoid arthritis in animal models. In vitro studies have shown that the cell-cycle inhibitor p16INK4a also exerts anti-inflammatory effects on rheumatoid synovial fibroblasts (RSF) in CDK activity-dependent and -independent manners. The present study was conducted to discern how p16INK4a modulates macrophages, which are the major source of inflammatory cytokines in inflamed synovial tissues. We found that p16INK4a suppresses LPS-induced production of IL-6 but not of TNF-α from macrophages. This inhibition did not depend on CDK4/6 activity and was not observed in RSF. p16INK4a gene transfer accelerated LPS-triggered IL-1R–associated kinase 1 (IRAK1) degradation in macrophages but not in RSF. The degradation inhibited the AP-1 pathway without affecting the NF-κB pathway. Treatment with a proteosome inhibitor prevented the acceleration of IRAK1 degradation and downregulation of the AP-1 pathway. THP-1 macrophages with forced IRAK1 expression were resistant to the p16INK4a-induced IL-6 suppression. Senescent macrophages with physiological expression of p16INK4a upregulated IL-6 production when p16INK4a was targeted by specific small interfering RNA. These findings indicate that p16INK4a promotes ubiquitin-dependent IRAK1 degradation, impairs AP-1 activation, and suppresses IL-6 production. Thus, p16INK4a senescence gene upregulation inhibits inflammatory cytokine production in macrophages in a different way than in RSF.

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…There is mounting evidence that the dysfunctional chondrocyte phenotype that emerges with aging and OA is characteristic of cellular senescence (McCulloch et al., 2017). While p16 INK4a is known to inhibit cellular proliferation with aging and senescence in many tissues, the lack of chondrocyte proliferation in vivo provides an opportunity to assess whether p16 INK4a plays a functional role in aging that is independent of cell cycle inhibition, as has been proposed in other physiological settings (Goel et al., 2017; Murakami et al., 2012). In this study, we found that p16 INK4a expression is an effective biomarker of chondrocyte dysfunction despite not being an essential mediator of age‐related or injury‐induced OA.…”

“…Furthermore, in vivo evidence suggests that the primary functional consequence of high p16 INK4a expression with aging is to limit the proliferation of specific cell types during homeostasis or in response to injury (Janzen et al., 2006; Krishnamurthy et al., 2006; Liu et al., 2011; Molofsky et al., 2006; Sousa‐Victor et al., 2014). Several groups, however, have suggested cell cycle independent effects of p16 INK4a and CDK4/6 inhibition (Goel et al., 2017; Murakami, Mizoguchi, Saito, Miyasaka & Kohsaka, 2012), and it is unclear whether reduced p16 INK4a expression can protect tissues from age‐related pathologies that are associated with the SASP but not with replicative failure.…”

Cellular senescence impact on immune cell fate and function

“…Indeed, Murakami et al . (2012) recently showed that p16 INK4a expression suppresses LPS‐induced production of IL‐6 in mouse and human macrophages.…”

Role of SNF5 in rheumatoid arthritis by upregulation ofp16 and inactivation of JNK pathway

“…Taniguchi et al found that introduction of p16 in the synovial fibroblast cells with the help of adenoviral gene therapy led to the suppression of disease progression in an animal model of RA (Taniguchi et al, 1999). Murakami et al concluded that p16, an inhibitor of cell cycle progression, showed antiinflammatory effects on rheumatoid synovial fibroblasts and its upregulation led to inhibition of inflammatory cytokine production from the macrophages (Murakami et al, 2012). Ultimately, these findings indicate a protective role of p16 in the suppression of the disease progression of RA.…”

“…Pannus releases inflammatory mediators locally and is responsible for destruction of the affected joints. Hence, inhibition of pannus formation would suppress the progression of RA (Sherr and Roberts, 1995;Taniguchi et al, 1999;Nasu et al, 2001;Nonomura et al, 2001Nonomura et al, , 2006Nishida et al, 2004;Choi et al, 2005;Murakami et al, 2012).…”