p16(INK4a) deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages

Université Lille Nord de France, Lille, France.
Blood (Impact Factor: 10.45). 06/2011; 118(9):2556-66. DOI: 10.1182/blood-2010-10-313106
Source: PubMed


The CDKN2A locus, which contains the tumor suppressor gene p16(INK4a), is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMϕ) or alternatively (AAMϕ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16(INK4a) deficiency (p16(-/-)) modulates the macrophage phenotype. Transcriptome analysis revealed that p16(-/-) BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4-induced macrophage polarization. In line with this observation, p16(-/-) BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16(-/-) BM displayed higher hepatic AAMϕ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMϕ phenotype skewing. Surprisingly, p16(-/-) BMDMs did not display increased IL-4-induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)-induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16(INK4a) as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.

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Available from: Réjane Paumelle, Sep 10, 2015
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    • "The main role of p16 is formation of inhibitory cdk4-6/p16 complexes, degradation of free Cyclin D by an ubiquitin-dependent proteasome pathway and subsequent inhibition of cell cycle progression 9. Besides its role in cancer as an inhibitor of cell-cycle progression, p16 plays important role in modulation of immune response 10. In response to DNA damage, wild-type p53 upregulates p21 (WAF1/Cip1) protein, which is a general inhibitor of CDKs and contributes to G1 cell cycle arrest under these circumstances 11. "
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