High expression of p21Waf1 in sarcoid granulomas: a putative role for long-lasting inflammation

Abstract

In sarcoid granulomas, apoptotic events are reduced, which explains their characteristic long-lasting inflammation. We have described that interferon-gamma (IFN-gamma) inhibits apoptosis in macrophages through the expression of p21(Waf1). Here, we explore the molecular mechanisms involved in the inhibition of apoptosis in sarcoid granulomas. We analyzed skin biopsies from 19 sarcoidosis patients and 16 controls. Total RNA was subjected to semiquantitative reverse transcriptase-polymerase chain reaction analysis. There was no difference found in the expression of proapoptotic (Bax and Bcl-X(s)) or antiapoptotic (Bcl-2 and Bcl-X(L)) genes nor in the expression of the tumor suppressor gene p53. Furthermore, the expression of IFN-gamma and the cdk inhibitors p21(Waf1) and p27(Kip1) were analyzed. IFN-gamma was detected in 37% of the sarcoidosis patients, and controls were negative (P<0.02). In addition, a higher proportion of patients expressing p21(Waf1) (58%) versus controls (12%) was found (P<0.005). There was a significant correlation between the expression of IFN-gamma and p21(Waf1) (r=0.69) and between p21(Waf1) and fibronectin (r=0.65). Finally, using immunohistochemistry, high p21(Waf1) reactivity was observed inside the granuloma. We conclude that the high levels of p21(Waf1) in sarcoidosis may explain the absence of apoptosis in the granuloma and the persistence of inflammation.

Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

“…DAP, an ubiquitin homology protein, has been shown to suppress NF-kB/Rel activity, to interact with the death domain of TNF-R1 (Tumor necrosis factor receptor 1) and to trigger program cell death in a variety of cell lines (Liou and Liou 1999;Raveh et al 2000). The potential relevance is that a balance between apoptosis and inXammatory cell survival provides a fundamental mechanism for immune system homeostasis and one proposed mechanism for the chronic granulomatous inXammation in sarcoidosis is through altered apoptosis (Mermigkis et al 2005;Xaus et al 2003;Stridh et al 2002). Granzymes A and K (GZM A and K), located on chromosome 5q11-12 approximately 1.5 cM from D5S407, are serine proteases released from the granules of cytotoxic lymphocytes which induce apoptosis and are expressed in PBMCs (Bade et al 2005).…”

The Serum Expression of Selected miRNAs in Pulmonary Sarcoidosis with/without Löfgren’s Syndrome

“…In addition, several particular target genes of the “Pathways in Cancer” have been indeed indicated in wet laboratory to be dysregulated at their protein and/or mRNA level in sarcoidosis [31–36]. Among them, WNT (wingless and integrase-1)7A, catenin-beta, and transforming growth factor- (TGF-) β are concurrently involved into other signalling pathways, including the WNT and TGF- β signalling pathways [23].…”

T cell contributions to the different phases of granuloma formation

“…AIM deficiency resulted in apoptosis of granuloma infiltrating T and NK T cells. Some have suggested that induction of p21 WAF by IFN-␥ could be a mechanism for the low apoptotic activity observed in sarcoid granulomas [52]. In addition to these specialized apoptotic signaling pathways, stimulation through the T cell receptor is known to affect T cell survival and proliferation, but this has not been directly studied within granulomas.…”