Papers of the Week

Alpha1-adrenoceptors are over-expressed in the epidermis of a subgroup of patients with complex regional pain syndrome (CRPS). Activating α1-adrenoceptors in epidermal cells increases production of the pro-inflammatory cytokine interleukin-6 (IL-6), a mediator of inflammation. To investigate whether this might exacerbate inflammation in CRPS, primary keratinocytes and/or dermal fibroblasts were cultured from skin biopsies obtained from the affected limb of 25 patients and a similar site in 28 controls. The fundamental pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), was administered for 24 hours to initiate inflammation. Following this, cells were incubated for 6 hours with the α1-adrenoceptor agonist phenylephrine. Exposure to TNFα induced pro-inflammatory cytokine mRNA production and protein secretion in keratinocytes and fibroblasts, and enhanced α1B-adrenoceptor mRNA expression in keratinocytes. Additional stimulation of α1-adrenoceptors with phenylephrine increased the production of interleukin-6 (IL-6) mRNA and protein secretion in both cell types. Under all conditions, gene and protein α1-adrenoceptor levels and cytokine gene expression and protein secretion were similar, overall, in patients and controls, except for abnormally high α1-adrenoceptor protein levels in the keratinocytes of three of 17 patients. These findings suggest that persistent inflammation in CRPS is not due to dysfunction of skin cells but is a normal response to extrinsic signals. After α1-adrenoceptor stimulation of keratinocytes, increases in IL-6 mRNA but not protein were proportional to basal α1-adrenoceptor protein levels. Skin cells play an important role in persistent inflammation in CRPS. Potentially, a positive feedback loop between α1-adrenoceptors and IL-6 production in skin cells contributes to this inflammatory state.