IL-8/IL-8 receptor expression in psoriasis and the response to systemic tacrolimus (FK506) therapy

Abstract

SUMMARY Recently, the keratinocyte IL‐8/IL‐8 receptor (IL‐8R) pathway has been implicated in the pathogenesis of psoriasis, and there is evidence that the potent macrolide immune suppressant tacrolimus (formerly FK506) can inhibit this pathway in vitro. In this study, determination of the expression of cytokine mRNAs in lesional skin of patients with active disease by reverse transcriptase polymerase chain reaction revealed transcripts for IL‐1β, tumour necrosis factor‐alpha (TNF‐α), IL‐6, IL‐8, IL‐8R, IL‐10, interferon‐gamma (IFN‐γ), IL‐2R and transforming growth factor‐beta (TGF‐β), but not IL‐2 or IL‐4. IL‐8 was the only cytokine expressed in affected skin of all patients but not in clinically normal skin of healthy subjects. In seven CD4+ T cell clones propagated from the lesional skin of an untreated psoriasis patient, IL‐8 was expressed by the skin‐derived T lymphocytes and not by feeder cells (irradiated autologous blood lymphocytes); IL‐1β, IL‐2, IL‐6 and IL‐10 were also expressed by some or all of the T cell clones, IL‐8 mRNA was not detected in the skin of any patient after the start of systemic tacrolimus therapy; IL‐lβ, IL‐6 and IFN‐γ transcripts were also reduced. By 12 weeks, the mean psoriasis area and severity index (PASI) had decreased from 18·8 to 3·8, a reduction of 80%. In the same post‐treatment biopsies, however, message for IL‐8R persisted. Estimation of circulating IL‐8 levels by enzyme immunoassay showed that all patients with detectable IL‐8 before treatment had decreased levels in response to treatment with tacrolimus; reductions in PASI scores were accompanied by decreases in IL‐8 levels, that varied both in rate and extent. Partial relapse, which in a minority of patients followed the initial period of remission, and was precipitated by drug dose reduction, was accompanied by an increase in circulating IL‐8. These findings add credence to the view that the IL‐8/IL‐8R autocrine/paracrine pathway may be important in the pathogenesis of psoriasis. They further suggest that interference with IL‐8 production and/or that of other key chemokines may be an important mechanism underlying the therapeutic efficacy of tacrolimus, and other agents such as cyclosporin A, with similar molecular actions.

Topical treatment of mild to moderate plaque psoriasis with 0·3% tacrolimus gel and 0·5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression

“…To date, to the best of our knowledge there are no studies available investigating the effect of topical tacrolimus on aspects of inflammation in lesional psoriatic skin. Nevertheless, systemic tacrolimus was studied and induced a reduction of interleukin (IL)-1b, soluble IL-2R (sIL-2), IL-6, IL-8 and interferon-c. [21][22][23] Furthermore our data are in agreement with a study by Thomson et al, who found a marked reduction of CD4+, CD8+ and a significant fall of CD25+ T cells in lesional psoriatic skin after 4-8 weeks of treatment with systemic tacrolimus. 24 In the present study tacrolimus gel had a highly significant effect on the IL-2 receptor (CD25) on T cells.…”

“…To date, to the best of our knowledge there are no studies available investigating the effect of topical tacrolimus on aspects of inflammation in lesional psoriatic skin. Nevertheless, systemic tacrolimus was studied and induced a reduction of interleukin (IL)‐1β, soluble IL‐2R (sIL‐2), IL‐6, IL‐8 and interferon‐γ 21–23 . Furthermore our data are in agreement with a study by Thomson et al.…”

Tacrolimus for the management of psoriasis: clinical utility and place in therapy

“…Tacrolimus also causes decreased transcription and release of other T-cell-derived cytokines including IL-3, IL-4, IL-8, TNF-α, INF-γ, and granulocyte macrophage colony-stimulating factor; it has also been found that exocytosis of in cytotoxic T-cells is inhibited by tacrolimus. 8 In vitro research has indicated that p53 levels in psoriatic skin are diminished; Lemster et al 8 describe augmentation of p53 gene expression by tacrolimus treatment, resulting in a reduced rate of epidermal hyperproliferation.…”

Development of TAP, a non-invasive test for qualitative and quantitative measurements of biomarkers from the skin surface

“…Type II biomarkers have been identified for various psoriasis and atopic dermatitis therapies, including biomarkers representing Th17 pathway [ 33 – 35 ], monocyte activity (e.g. TNF-α) [ 31 ], lymphocyte activity (Granzyme B) and type I interferon pathways [ 16 – 24 ]. Of particular interest is a study by Malaviya et al ., showing that the amount of cleaved Caspase-3-positive cells, accurately predicts response to Enbrel, months before response to therapy can be assessed based on clinical symptoms [ 25 ].…”