Lack of expression of interleukin 8 and RANTES in autoimmune bullous skin diseases.

BACKGROUND: In autoimmune bullous skin diseases, accumulation of neutrophils and/or eosinophils in the affected skin represents a characteristic feature. So far, however, the induction of this granulocyte infiltration has not been elucidated. OBJECTIVE: Regarding their biological effects, the chemokines interleukin 8 (IL-8) and RANTES (regulated upon activation normal T lymphocyte expressed and secreted) could play a role in this granulocyte accumulation. METHODS: Immunohistochemical examination of lesional skin from patients with bullous pemphigoid, pemphigus, dermatitis herpetiformis and linear IgA disease was performed using a set of different antibodies against IL-8 and RANTES. Additionally, blister fluids were screened for soluble RANTES peptide using an ELISA. RESULTS: No difference in chemokine expression was found in lesions of autoimmune bullous diseases compared to normal skin. CONCLUSION: In contrast to chronic inflammatory diseases like psoriasis and eczema, where keratinocyte IL-8 immunoreactivity was found to differ from normal skin, keratinocyte immunoreactivity is not altered in autoimmune bullous diseases.

The CXC receptor 2 is overexpressed in psoriatic epidermis.

The CXC chemokines interleukin-8 and GRO/melanoma growth-stimulatory activity (GRO-alpha) are potent activators of neutrophils and lymphocytes, but also stimulate growth and differentiation of nonhematopoietic cells like keratinocytes, fibroblasts, and melanocytes. High mRNA and protein levels have been detected in psoriatic epidermis. Chemokine activation of target cells is mediated by specific receptors and two CXC receptors have been described with similar affinity for interleukin-8 but different affinities for GRO-alpha. In this study, we examined the expression of both CXCR1 and CXCR2 in psoriatic tissue, identifying the target cells of chemokine activation in psoriasis. By immunohistochemistry and in situ hybridization, as confirmed by northern blot analysis and reverse transcriptase polymerase chain reaction, we could detect expression of the CXCR2 in suprabasal lesional psoriatic keratinocytes but not in healthy skin. The CXCR1 could not be localized in psoriatic keratinocytes with immunohistochemistry and in situ hybridization, but infiltrating cells in the dermal compartment expressed both types of receptors. These data suggest that in addition to neutrophil activation by both CXCR1 and CXCR2, activation of keratinocytes mediated by CXCR2 could contribute to the characteristic epidermal changes observed in psoriasis.

Interleukin-8 immunoreactivity in malignant tumours of the skin.

In the past, interleukin-8 (IL-8) could be demonstrated within keratinocytes in normal epidermis and inflammatory skin diseases, like psoriasis and eczema. Using monoclonal antibodies, the distribution of IL-8 immunoreactivity was inversely related to the density of inflammatory infiltrate. Other in vitro observations indicated IL-8 to be a growth factor for keratinocytes. These results prompted an immunohistochemical examination of IL-8 immunoreactivity in malignant and semimalignant epithelial tumours of human skin. Whereas IL-8 could not be detected within the transformed cells of epithelial tumours or melanoma, some tumour cells within well differentiated squamous cell carcinoma and Bowen's disease showed IL-8 immunoreactivity. Thus, loss of IL-8 immunoreactivity can be a sign of malignant transformation. This indicates an important role in growth regulation as well as terminal differentiation of human keratinocytes.

Detection of the chemokine RANTES in cytokine-stimulated human dermal fibroblasts.

A novel family of structurally and functionally related polypeptides has recently been detected that are now referred to as chemokines. Within this family, a peptide with the acronym RANTES was shown to be chemotactic for memory T cells, monocytes, and eosinophilic and basophilic granulocytes, thus suggesting it plays an important role in chronic inflammatory and allergic diseases. Murine monoclonal antibodies as well as cDNA probes specific for human RANTES were raised and extensively characterized. With these antibodies, stimulated human dermal fibroblasts were shown to express intracellular RANTES peptide by immunocytochemistry. Furthermore, similar kinetics could be demonstrated in fibroblasts for both RANTES mRNA expression and secretion of RANTES peptide using Northern blot hybridization and sandwich-enzyme-linked immunosorbent assay, respectively. RANTES expression was induced upon stimulation with tumor necrosis factor-alpha as well as with interleukin-1 alpha and -beta in a concentration- and time-dependent manner. These results reinforce the role of both resident and circulating cells in the production and release of RANTES and their participation in inflammatory processes.

Immunohistochemical studies on NAP-1/IL-8 in contact eczema and atopic dermatitis.

The neutrophil activating peptide NAP-1/IL-8 has in the past been shown to be secreted by diverse cell-types involved in inflammatory processes. Furthermore, potent biological effects on both neutrophilic granulocytes and lymphocytes enforce its role in inflammation. Recently, immunohistochemical studies using monoclonal anti-NAP-1/IL-8 antibodies have been performed on dermal inflammatory conditions like psoriasis vulgaris. These have demonstrated epidermal IL-8 immunoreactivity in a pattern inversely related to the degree of inflammatory infiltration. Based on these results, in the present study biopsies from patients with contact eczema as well as atopic dermatitis were examined. The same patterns of immunoreactivity were found with either homogeneous epidermal staining, focally negative staining or overall decreased or even absent staining. As in psoriasis, these patterns were related to the degree of inflammatory infiltration. These results prove NAP-1/IL-8 to be involved not only in psoriasis vulgaris, but more likely to be a marker of different inflammatory processes. Future work will have to examine the kinetics as well as stimuli causing these effect.

Localization of neutrophil-activating peptide-1/interleukin-8-immunoreactivity in normal and psoriatic skin.

Various cytokines have in the past been detected in human skin. Among these, the neutrophil-activating peptide NAP-1/IL-8 is a potent 8-kD proinflammatory peptide that has been purified from psoriatic scales. Its chemotactic activity on human neutrophils, as well as its presence in psoriatic scales, may relate to a role in this disease. In the present study, the tissue distribution of the peptide was examined immunohistochemically using two monoclonal antibodies (52E8, 46E5) recently produced and characterized in our laboratory. Immunoreactivity was detected in both normal and psoriatic skin, resulting in uniform suprabasal keratinocyte staining in normal skin with 52E8 and of all keratinocytes with 46E5. Immunoreactivity in psoriasis correlated to the inflammatory tissue reaction, varying from uniform absence in highly active psoriasis to focally weak staining in plaque type psoriasis. Cells of the acrosyringium and hair follicles were always positive and were unaffected by the inflammatory activity. Epidermal immunoreactivity detected in this study may be associated with closely related peptides of the IL8 family or with truncated or extended forms of NAP-1/IL-8.