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.


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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    ABSTRACT: Objective. Progression from ulcerative colitis (UC) toward colorectal carcinoma (CRC) is multistep process that includes gene alterations of tumor suppressor genes, such as p53 and p16. The aim of this study was to investigate the expression patterns of p16, p53 and VEGF in affected tissue and serum levels of cytokines TNF-α, IFN-γ, IL-4, IL-6, IL-10 and IL-17 in patients with UC and CRC, respectively. Matherials and methods. Serum levels of cytokine in patients with UC (n=24) and CRC (n=75) and in a healthy group (n=37) were analyzed by ELISA. Endoscopic biopsies specimens of UC and CRC were studied by immunohistochemical staining for p16, p53 and VEGF. Results. Patients with UC with presence of extraintestinal manifestations, complications, and positive staining of p16, p53 and VEGF respectively had higher serum levels of pro-inflammatory cytokines. Higher percentage of CRC patients had positive staining of p16, p53 and VEGF. CRC patients with positive staining of VEGF had decreased systemic values of pro-inflammatory IFN-γ and increased values of immunosuppressive IL-10. Conclusions. Relatively low IL-10 in patients with severe UC is insufficient to compensate IL-6 secretion and subsequently enhanced type 1/17 immune response. In UC patients, p16 and p53 induce enhanced VEGF expression and subsequent production of pro-inflammatory TNF-α and IL-6. In CRC patients VEGF seems to have immunosuppressive role. It appears that tumor suppressor gene-VEGF axis have dual role on immune response in inflammation of UC and tumor growth and progression of CRC.
    International journal of medical sciences 07/2014; 11(9):936-47. DOI:10.7150/ijms.8277 · 2.00 Impact Factor
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    • "Although the overall zero effect on atherosclerosis is surprising at first sight, it has been observed before that deficiency of proteins with an important role in inflammatory signalling and biological processes does not induce any changes in the size or composition of atherosclerotic lesions, as for example described for BM-deficiency of Cd40 ligand [59], [60] or Traf6 [61]. Also, atherosclerosis was not affected in Ldlr−/− mice with a BM p16INK4a-deficiency [62], despite the fact that p16INK4a is a regulator of macrophage activation and polarization and p16INK4a-deficiency reduces LPS-induced NF-κB activation in BM-derived macrophages [63]. Clearly, it would be interesting to address in the future the role of the IKKα kinase in atherosclerosis in different leukocyte subsets individually and in vascular cells. "
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    PLoS ONE 02/2014; 9(2):e87452. DOI:10.1371/journal.pone.0087452 · 3.23 Impact Factor
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    • "Saberi et al. showed that hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates adipose tissue insulin resistance in HCD-fed mice, using BMC-transplanted chimeric mice [36]. Cudejko et al. demonstrated that p16INK4a deficiency modulates macrophage polarization, using BMC chimeric mice [37]. Accordingly, we performed bone marrow transplantation of ATIP1-Tg using KKAy mice as recipients. "
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    PLoS ONE 04/2013; 8(4):e60067. DOI:10.1371/journal.pone.0060067 · 3.23 Impact Factor
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