Thalidomide inhibits UVB‐induced mouse keratinocyte apoptosis by both TNF‐α‐dependent and TNF‐α‐independent pathways

Abstract

Thalidomide has been shown to selectively inhibit TNF-α production in vitro by lipopolysaccharide (LPS)-stimulated monocytes. TNF-α has been shown to play a pivotal role in the pathophysiology of endotoxic shock. Using a mouse model of LPS-induced shock, we investigated the effects of thalidomide on the production of TNF-α and other cytokines and on animal survival. After injection of 100-350 µg LPS into mice, cytokines including TNF-α, IL-6, IL-10, IL-1ß, GM-CSF and IFN-γ were measured in the serum. Administration of 200 mg/kg thalidomide to mice before LPS challenge modified the profile of LPS-induced cytokine secretion. Serum TNF-α levels were reduced by 93%, in a dose-dependent manner, and TNF-α mRNA expression in the spleens of mice was reduced by 70%. Serum IL-6 levels were also inhibited by 50%. Thalidomide induced a twofold increase in serum IL-10 levels. Thalidomide treatment did not interfere with the production of GM-CSF, IL-1ß or IFN-γ. The LD 50 of LPS in this model was increased by thalidomide pre-treatment from 150 µg to 300 µg in 72 h. Thus, at otherwise lethal doses of LPS, thalidomide treatment was found to protect animals from death. Correspondence A.L. Moreira

C1q: Its Functions within the Innate and Adaptive Immune Responses and its Role in Lupus Autoimmunity

“…Since binding of C1q to the CD91-calreticulin complex on other apoptotic cell types has been shown to facilitate their phagocytic removal via macropinocytosis (Ogden et al, 2001;Vandivier et al, 2002), it has been tempting to speculate that the same might be true for UV-B induced apoptotic epidermal keratinocytes. This would be consistent with the observation that apoptotic epidermal keratinocytes are increased in LE skin lesions (Chung et al, 1998;Pablos et al, 1999) and the fact that drugs such as thalidomide that are highly efficacious clinically in cutaneous LE have been shown to inhibit the formation of apoptotic epidermal keratinocytes following UV-B irradiation (Lu et al, 2003). One report, indicates that the rate of clearance of UV-B-induced apoptotic epidermal keratinocytes did not differ significantly from that of C1q replete mice (Pickering et al, 2001).…”

Cutaneous lupus erythematosus: A personal approach to management

“…Its mechanism of action is believed to involve decrease in inflammatory mediators, particularly TNF‐α and Fas‐ligand. It has been recently demonstrated in a murine system that thalidomide inhibits UVB‐induced keratinocytes apoptosis 92 . These observations were extended to humans in a study of photoprotective effects of thalidomide 93 .…”

Human and Murine Evidence for Mechanisms Driving Autoimmune Photosensitivity

“…Murine cytokine production after UVB is similar to that seen in human skin: TNFα, IL-6, IL-1, IL-23, and type I IFNs are all increased ( 139 , 142 , 149 ). Most of the cytokine induction is fairly rapid: TNFα and IL-6 production occurs 8–24 h after UVB exposure ( 150 ).…”