UVA1 radiation attenuates pro-inflammatory functions in human monocytes.

UVA1 therapy is effective in the treatment of inflammatory and autoimmune skin diseases. The mode of action of UVA1 therapy is not completely understood and especially data on cells of the innate immune system like monocytes, which are critically involved in many inflammatory processes, are sparse. We wanted to answer the question whether UVA1 irradiation alters functional properties of human monocytes. We treated human peripheral blood monocytes in vitro with 2 J/cm2 UVA1 light, incubated the cells for 48 h and examined both functional properties and alterations in the gene and protein expression profile. While UVA1 did not alter cell viability or susceptibility to apoptosis inducing agents, it decreased the capacity of monocytes for phagocytosis and to eliminate infectious agents like Leishmania major. Moreover, we measured a significantly reduced production of interleukin (IL)-1ß mRNA in lipopolysaccharide activated monocytes after UVA1 treatment. Importantly, UVA1-treated monocytes not only produce less IL-1ß, but also upregulate expression of the anti-inflammatory IL-1ß decoy receptor. Our data provide evidence that UVA1 radiation not only interferes with fundamental monocyte properties like phagocytosis, pathogen killing and activation, but could also specifically attenuate pro-inflammatory IL-1 effects. This might constitute a hitherto unknown anti-inflammatory mechanism of UVA1 in human monocytes.

The cyclic AMP response element modulator regulates transcription of the TCR zeta-chain.

Systemic lupus erythematosus T cells display decreased amounts of TCR zeta mRNA that results in part from limited binding of the transcriptional enhancer Elf-1 to the TCR zeta promoter. We have identified a new cis-binding site for the cAMP response element (CRE) modulator (CREM) on the TCR zeta promoter, centered on the -390 nucleotide. Transfection of T cells with an antisense CREM alpha plasmid reduced the binding of CREM to the TCR zeta promoter, as shown by chromatin and reporter chromatin immunoprecipitation assays, and enhanced the production of TCR zeta mRNA and protein. Mutagenesis of the -390 CRE site prevented the binding of CREM to the TCR zeta promoter. The mechanism of CREM-mediated repression appears to be chromatin dependent, because antisense CREM promotes the acetylation of histones on the TCR zeta promoter. Finally, we established an enhanced binding of CREM to the TCR zeta-chain promoter in systemic lupus erythematosus cells compared with control T cells. Our studies demonstrate that CREM alpha binds to the TCR zeta promoter and repress its activity.