UVR Induces the Release of Proapoptotic Cytokines

UVR alters the expression of cytokines and adhesion molecules in the skin to cause apoptosis and inflammation. Primary cytokines released by keratinocyte cells in response to UVB are IL-1 and TNF-a (Norris et al. 1997). TNF-a and IL-1a have been demonstrated to cause increased production of TNF-a by keratinocytes in an autocrine manner (Lisby and Hauser 2002). Interestingly, TNF-a induces apoptosis and the translocation of intracellular Ro and La antigens to surface blebs on cultured keratinocyte cells (Dorner et al. 1995a). Early studies searching for candidate genes involved in SLE demonstrated that a polymorphism in the promoter region of TNF-

Table 18.1. Prevalence of the -308A polymorphism in cutaneous lupus erythematosus (CLE)




















-308A frequency




DLE, discoid LE; SCLE, subacute CLE.

DLE, discoid LE; SCLE, subacute CLE.

a, termed "TNF2",was strongly linked to HLA-A1, -B8, and -DR3 (Wilson et al. 1993). Subsequent studies showed that this promoter polymorphism, which consisted of a substitution of guanine by adenosine at the -308 base pair in the promoter region of TNF-a, was more common in patients with SLE than in controls, but the linkage was not independent of the DR3 haplotype (Wilson et al. 1994). HLA-DR3 but not the -308A polymorphism is strongly linked to the presence of anti-Ro/SSA and anti-La/SSB autoantibodies (Wilson et al. 1994).

The TNF2 polymorphism has subsequently been demonstrated to act as an independent susceptibility factor from the DR3 locus for SLE in two separate cohorts of African American (Sullivan and Furst 1997) and Caucasian (Rood et al. 2000) patients with SLE. Studies on human B cells transfected with the CAT reporter gene under the control of the TNF2 promoter have an increase in transcription compared with TNF1 promoter, demonstrating that the polymorphism may impact autoimmunity via production of increased TNF-a (Wilson et al. 1997). TNF-a levels do not differ between patients with active or clinical remission (Wais et al. 2003).

The TNF2 promoter is also linked to photosensitive cutaneous autoimmune disease. Patients with SCLE have an increased prevalence of the -308A promoter vs controls, and the -308A polymorphism is linked to DR3 in patients with SCLE but not with DM (Millard et al. 2001, Pachman et al. 2000,Werth et al. 2000,2002) (Table 18.1). Patients with DLE do not have a statistically significant increase in TNF2 (Millard et al. 2001, Werth et al. 2000). In vitro assays using the CAT-construct under control of the full-length TNF1 promoter demonstrate that KCs produce TNF-a in response to IL-1a and TNF-a (Lisby and Hauser 2002). Further studies demonstrated that -308A is a much stronger transcriptional activator than the -308G wild-type promoter in UVB- but not UVA-irradiated KCS (Silverberg et al. 1999) and fibroblasts in the presence of IL-1a (Werth et al. 2000).

The functional link between photosensitive disease and the TNF2 promoter is still unclear, but it may be that increased production of TNF-a in response to UV light leads to an increase in apoptotic cells and inflammatory mediators. In the right MHC background, this increase in apoptotic cells may overwhelm the noninflammatory clearance of apoptotic debris and may lead to the development of autoantibodies.

IL-12 may also have a role in controlling UV-mediated apoptosis. Both UVA and UVB induce IL-12, and IL-12 causes suppression of TNF-a at the level of the promoter (Werth et al. 2003). Interestingly, IL-12 was found to promote survival of UV-irradi-ated keratinocytes in vivo, likely by increasing the activity of DNA repair enzymes (Schwarz et al. 2002). It is tempting to speculate that UVA1-induced IL-12 may be responsible for inhibition of TNF-a, possibly working through DNA repair enzymes, and thus accounting for the therapeutic effects of UVA1 seen in particular with anti-Ro/SSA-positive photosensitive LE patients (McGrath 1994).

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