Article

Inflammation in mice ectopically expressing human PAPA syndrome-associated PSTPIP1 A230T mutant proteins.

University of Massachusetts Medical School, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2013; 288(7). DOI: 10.1074/jbc.M112.443077
Source: PubMed

ABSTRACT Pyogenic Arthritis, Pyoderma Gangrenosum and Acne Syndrome (PAPA syndrome) is an autoinflammatory disease caused by aberrant production of the proinflammatory cytokine interleukin-1. Mutations in the gene encoding proline serine threonine phosphatase interacting protein-1 (PSTPIP1) have been linked to PAPA syndrome. PSTPIP1 is an adaptor protein that interacts with PYRIN, the protein encoded by the Mediterranean Fever (MEFV) gene whose mutations cause Familial Mediterranean Fever (FMF). However, the pathophysiological function of PSTPIP1 remains to be elucidated. We have generated mouse strains that either are PSTPIP1 deficient or ectopically express mutant PSTPIP1. Rusults from analyzing these mice suggested that PSTPIP1 is not an essential regulator of the Nlrp3, Aim2 or Nlrc4 inflammasomes. Although common features of human PAPA syndrome such as pyogenic arthritis and skin inflammation were not recapitulated in the mouse model, ectopic expression of the mutant but not the wild type PSTPIP1 in mice lead to partial embryonic lethality, growth retardation and elevated level of circulating proinflammatory cytokines.

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    • "A deregulation of caspase-1 activation and an increased production of IL-1b as well as tumor necrosis factor in peripheral blood mononuclear cells have been reported (Shoham et al., 2003; Cortis et al., 2004). PSTPIP1 mutants have been shown to induce proIL-1b processing by caspase-1 (Yu et al., 2007; Wang et al., 2013) and Anakinra has been shown to be effective in the control of inflammatory manifestations in certain patients (Dierselhuis et al., 2005; Brenner et al., 2009). "
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