*The Key Role of I*κ*B*α *in NF-*κ*B Modulation in pSS*

Among the well-characterized regulators of NF-κB activation in SGEC, IκBα is particularly important for the pathogenesis of pSS. The concept that IκBα expression negatively regulates NF-κB DNA binding activity was demonstrated by the fact that reduced IκBα overlaps with nuclear translocation of the NF-κB and the appearance of NF-κB activity [55]. For SGs, adenoid cystic carcinoma of human SGs cell lines, stably transfected with the mutant IκBα expression vector (IκBαM) share an effectively cancelled constitutive and liposaccharide-induced NF-κB activity, concomitantly with a significantly diminished VEGF gene and protein expression. This effect leads to a lower endothelial cell mobility and, thus, might represent a promising anti-angiogenesis strategy in adenoid cystic carcinoma (ACC) therapy [56]. In pSS SGEC, abnormal levels of IκBα were detected in comparison with those in healthy subjects, showing a clear reduction of IκBα in salivary tissues from active pSS patients [19]. This was confirmed in biopsy specimens, where a moderate IκBα positive staining

located in the cytoplasm of acini and ductal cells was revealed in healthy controls, whereas in pSS salivary gland biopsies the cytoplasmic positivity for IκBα was very weak [19]. All of this suggests that the production of proinflammatory cytokines occurs through the persistent activation of NF-κB signalling [17,18,25,26]. In addition, a reduced gene and protein expression of IκBα was demonstrated in monocytes from pSS patients in comparison with healthy subjects, suggesting that the reduced expression of this NF-κB inhibitor may reflect an increased inflammatory response [26]. Specifically, published data show that mutations in IκBα are linked to inflammatory autoimmune disorders. An 8-bp insertion in the promoter region of IκBα represents a protective factor against the development of primary progressive multiple sclerosis [57]. Klein et al. showed that IκBα polymorphisms might also be associated with Crohn's disease [58], SLE [59] and pSS [47,48]. In particular, mutant mice, that have defective IκBα expression, showed a shorter lifetime, hypersensitivity to septic shock and altered T cell development, all features of pSS [47,48]. Furthermore, overexpression of the NF-κB repressor, IκBα, determines an inhibitory effect on the production of STAT-4 protein, a transcription factor activated by interleukin 12 whose gene polymorphism was recently linked to pSS [60,61].

NF-κB signalling activation and termination is secured by various regulatory processes. In view of the well-characterized links between NF-κB and pSS disease, disentangling the complexity of NF-κB modulation is an essential goal in order to find effective, more specific therapeutic agents for the treatment of pSS.
