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  • br CDK Regulators as Coactivators of NF B


    CDK Regulators as Coactivators of NF-κB and STAT CDK regulating proteins also have the ability to control the inflammatory response. The p21CIP1 protein binds to and inhibits the activity of cyclin–CDK4/6 and cyclin–CDK1/2 complexes. Consistent with its ability to inhibit CDK activity, deletion of the p21CIP1-encoding Cdkn1a gene can lead to increased CDK activity, elevated NF-κB activity, and production of proinflammatory mediators such as TNF and IL-1. Accordingly, Cdkn1a knockout mice show greater sensitivity to LPS-induced septic shock [52]. This p21CIP1-dependent effect crucially depends on the CDK-binding domain of p21CIP1, suggesting that exaggerated cytokine production in p21CIP1-deficient A 350619 hydrochloride is CDK-dependent. Similar results were obtained in p21CIP1-depleted human macrophages, showing that the anti-inflammatory function of p21CIP1 is not restricted to the murine system [53]. These findings are also of pathophysiological relevance because p21CIP1 expression is frequently diminished in synovial tissue in patients suffering from RA, and p21CIP1 is essential for the resolution of inflammatory arthritis [54]. In summary, these studies clearly show an anti-inflammatory role of the p21CIP1 protein, but formal proof for a central role of CDK activity in this process is still missing. Consistent with the notion of proinflammatory CDK signaling, expression of the CDK inhibitory p16INK4A protein in synovial fibroblasts also inhibits the development of RA [55]. Ectopic expression of p16INK4A also suppressed LPS-induced IL-6 expression in macrophages [56], reinforcing the observations that CDK inhibitory proteins function to counteract inflammation.
    Do the Proinflammatory Roles of CDK Regulators Depend on Cell Cycle Regulation? In most pathophysiological situations inflammation is not associated with proliferative processes. Within the first hours after infection, specialized and terminally differentiated cells such as macrophages sense invading pathogens with their PRRs and trigger a massive release of inflammatory mediators. In this situation, the proinflammatory role of CDKs occurs independently from its ability to trigger cell proliferation, which is even suppressed by LPS in macrophages [57]. However, some cell cycle-regulated processes may occur in the absence of cell proliferation. An example of such a scenario is provided by the analysis of gene expression in various cell cycle phases of HeLa cells. Some TNF-induced genes such as IL8 are preferentially expressed during G1/S transition and to a lesser extent during the other cell cycle phases [36]. The same study also revealed that the expression of other TNF-triggered genes is not influenced by the cell cycle. It will thus be very interesting to reveal the relative contribution of cell cycle phases for the entire set of inflammatory gene expression by genome-wide analyses. The situation is markedly different in other situations where inflammation is associated with a proliferative response. This is exemplified by the invasive pannus tissue in the joints of RA patients that consists of proliferating synovial fibroblasts. Upon growth factor signals, these cells divide and increase their capacity to secrete a variety of inflammatory cytokines [58]. For many decades anti-proliferative and anti-inflammatory agents such as cyclophosphamide, azathioprine, methotrexate, and leflunomide have been used to treat severe forms of autoimmune diseases including RA [59]. These drugs are immunosuppressive by blocking clonal expansion of T and B cells. However, owing to their nonspecific cytostatic action they also affect tissue proliferation. This effect may directly contribute to local reduction of inflammatory mediators [60], and suggests a link between cell cycle and ongoing inflammation. Indeed, a herpesvirus-encoded cyclin that binds to and activates CDK6 is associated with Kaposi sarcoma, a tumor characterized by endothelial cell proliferation and inflammation 61, 62.