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- Hallermalm, K, et al.
(författare)
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Tumor necrosis factor-alpha induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface
- 2001
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 98:4, s. 1108-1115
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Tidskriftsartikel (refereegranskat)abstract
- It is demonstrated that similar to interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α) induces coordinated changes at different steps of the major histocompatibility complex (MHC) class I processing and presentation pathway in nonprofessional antigen-presenting cells (APCs). TNF-α up-regulates the expression of 3 catalytic immunoproteasome subunits—LMP2, LMP7, and MECL-1—the immunomodulatory proteasome activator PA28α, the TAP1/TAP2 heterodimer, and the total pool of MHC class I heavy chain. It was also found that in TNF-α–treated cells, MHC class I molecules reconstitute more rapidly and have an increased average half-life at the cell surface. Biochemical changes induced by TNF-α in the MHC class I pathway were translated into increased sensitivity of TNF-α–treated targets to lysis by CD8+ cytotoxic T cells, demonstrating improved presentation of at least certain endogenously processed MHC class I–restricted peptide epitopes. Significantly, it was demonstrated that the effects of TNF-α observed in this experimental system were not mediated through the induction of IFN-γ. It appears to be likely that TNF-α–mediated effects on MHC class I processing and presentation do not involve any intermediate messengers. Collectively, these data demonstrate the existence of yet another biologic activity exerted by TNF-α, namely its capacity to act as a coordinated multi-step modulator of the MHC class I pathway of antigen processing and presentation. These results suggest that TNF-α may be useful when a concerted up-regulation of the MHC class I presentation machinery is required but cannot be achieved by IFN-γ.
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- Iles, Mark M., et al.
(författare)
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A variant in FTO shows association with melanoma risk not due to BMI
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:4, s. 428-432
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Tidskriftsartikel (refereegranskat)abstract
- We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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