Erratum

ARTICLE

Auteur(s) : Roddie C MCKENZIE¹, Elizabeth SABIN¹, Jacek C SZEPIETOWSKI², J Alastair GRACIE⁴, Rosalyn J FORSEY⁴, Sarah HOWIE³

Erratum

We apologise for an error which appeared in this letter in vol. 13 Nr 1, pages 100-101. We print below the correct version:

Dear Editor,

We read with great interest the recent paper by Koga et al. [1] showing the presence of IFN-γ immunostained cells in the psoriatic epidermis, which the authors take to be evidence for the presence of IFN-γ producing epidermal T-cells in psoriasis. This is indisputable. However, it seems to us that the authors have overlooked another very interesting finding ; that is the expression of IFN-γ by keratinocytes in the epidermis of psoriatic patients. In particular, in Fig. 2 and Fig. 3 of their paper [1], it seems that there is a significant amount of positive IFN-γ immunostaining within the cytoplasm of keratinocytes. This surely cannot be background or non-specific staining? We note that in another study [2] published in this journal, that micrographs of lesional psoriatic skin showing strong epidermal IFN-γ-immunostaining, which was decreased by mometasone furoate treatment, were shown. Remarkably, the authors of that study also failed to remark on what would also appear to be expression of IFN-γ by psoriatic keratinocytes.
We have noted that keratinocytes derived from non-lesional skin of psoriasis patients [3] and grown in serum free keratinocyte growth medium can produce significant amounts of secreted IFN-γ which can be measured by ELISA in the culture supernatants. Keratinocyte cultures (80% confluent) were harvested from 25 cm² flasks containing 10 mls of KSFM growth media [3]. Keratinocyte cultures from five different normal donors prepared by the same method [3] did not secrete any detectable IFN-γ using an ELISA with a detection limit of 3 pg/ml. However, two of four cultures from psoriatic patients produced readily detectable IFN-γ (mean = 32 ± 12 pg/ml). These cells had been cultured for 3-5 passages and cultures did not contain any T-cells.There is no record of human fibroblasts or melanocytes producing IFN-γ, so keratinocytes would seem the most likely source of the cytokine.
The question remains what induces IFN-γ production in keratinocytes? Ourselves and others have shown that keratinocytes can produce interleukin (IL)-18 [4-7], and that in lesional psoriasitic skin there is strong epidermal immunostaining for IL-18 [7, 8]. We found staining through out the spinous and basal layers. There was a corresponding 2.7-fold increase in IL-18 mRNA over levels in normal skin, as measured by RT-PCR, in 14 patients [7]. IL-18 immunostaining is absent in normal skin, but is also present in the basal layer of non-lesional psoriatic skin. The basal layer of the epidermis is where the dividing cells which establish in vitro keratinocyte cultures originate from.
IL-18 participates in a number of inflammatory conditions including rheumatoid arthritis where it can contribute to disease pathology by inducing pro-inflammatory mediators such as IFN-γ and TNF-β (reviewed in [9]). In addition, previously we have reported that psoriatic lesional epidermis expresses 5.2-fold higher levels of mRNA, for the IL-18 receptor measured by RT-PCR [7]. A possibility is that autocrine IL-18 release stimulates IFN-γ expression in psoriatic keratinocytes. The chemokines IP-10, MCP-1 and RANTES; the adhesion molecule ICAM-1; and HLA-DR are induced in keratinocytes by IFN-γ and are expressed at high levels in psoriatic epidermis (reviewed in [10]). If keratinocyte damage induces IL-18, followed by IFN-γ, this would provide an autocrine amplification loop for epidermal inflammation. What induces the IL-18? Keratinocyte damage by microbes? Or by other environmental agents? We know that some of these (streptococcal infection and physical trauma) are involved in triggering psoriasis. 
There are some previous reports of IFN-γ expression by keratinocytes. Basal keratinocytes in biopsies from lichen planus patients express IFN-γ mRNA [11] as do kerati nocytes in skin from contact sensitisation reactions [12]. In the latter study, IFN-γ protein was also detected by immunostaining and was co-localised with cytokeratin expression. IL-18 expression is induced in keratinocytes in vitro by contact sensitisers [13]. Moreover, the expression of IFN-γ by keratinocytes may be important in determining the development of the T-helper cell development down the TH-1 pathway, which is seen in psoriasis. For many years a dogma has persisted that IFN-γ is an exclusively “T-cell cytokine”. We would like to propose that this is an outmoded concept and that under conditions of extreme inflammation, that the keratinocyte-psoriatic or otherwise- can also express IFN-γ and direct the course of T-cell activation in the skin. 

Acknowledgements. We would like to thank The Psoriasis Association (UK) and the Foundation for Skin Research (Edinburgh) for funding these studies and Felicity Boyd for performing RT-PCR. n

References

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