Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes.

Grossman, Rachel; Krueger, James G.; Yourish, Debra; Granelli‐Piperno, Angela; Murphy, Daniel P.; May, Lester T.; Kupper, Thomas S.; Sehgal, Pravinkumar B.; Gottlieb, Alice B.

doi:10.1073/pnas.86.16.6367

Cited by 783 publications

(486 citation statements)

References 19 publications

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“…The ability of the CD40 pathway to induce IL6 secretion in epithelial cells and the e ects of IL6 on epithelial cell growth suggest that the growth-regulatory properties of CD40 signalling may be partly mediated by this cytokine. Interestingly, IL6 has been shown to inhibit the growth of certain carcinoma and leukemic cell lines (Clark & Shu, 1990;Chen et al, 1991;Takizawa et al, 1993) whilst normal human keratinocytes cultured in the absence of growth factors can be induced to proliferate in response to low concentrations of IL6 (Grossman et al, 1989). This suggests that the epithelial cell phenotype and di erentiation status may a ect the responsiveness of the cells to IL6 and thus to the consequences of CD40 ligation.…”

Section: Discussionmentioning

confidence: 96%

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

et al. 1997

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Expression of the Epstein ± Barr virus (EBV) transforming LMP1 in B cells activates the transcription factor NF-kB and induces phenotypic changes through two distinct domains in the cytoplasmic C-terminus of the protein. The aa 187 ± 231 domain of LMP1, which is important for growth transformation, binds tumour necrosis factor (TNF) receptor associated factor (TRAF) 1 and TRAF3 and this interaction mediates subsequent signalling events. The TRAFs also associate with CD40, a member of the TNFR family, which upon ligation activates NF-kB and induces phenotypic changes similar to those mediated by LMP1. This study demonstrates that LMP1 expression in carcinoma cell lines and SV40-transformed keratinocytes results in induction of the pleiotropic cytokine interleukin 6 (IL6), an e ect which is also observed upon CD40 ligation. The mechanism by which either LMP1 expression or CD40 ligation induces IL6 production was found to be NF-kB-dependent. Mutational analysis identi®ed domains in the C-terminus of LMP1 which are important for NF-kB activation and IL6 secretion. LMP1 and CD40 share a common PxQxT core TRAF binding motif and mutations in or adjacent to this sequence impaired the ability of LMP1 or CD40 to induce NF-kB activation and IL6 secretion. The importance of TRAF interactions in mediating these e ects was con®rmed using dominant negative TRAF2 and TRAF3 mutants which also identi®ed di erences in the signalling events mediated by the two NF-kB activating domains of LMP1. A20, an anti-apoptotic protein which interacts with TRAF2 and blocks CD40-mediated NF-kB activity, also blocked NF-kB and IL6 secretion in LMP1-transfected epithelial cells. These results suggest that LMP1 regulates IL6 production in epithelial cells in a manner similar to CD40 ligation and implicate TRAFs as common mediators in the transduction of signals generated via the CD40 and LMP1 pathways. As a role for IL6 in regulating epithelial cell growth has previously been suggested, the control of IL6 secretion via the CD40 and LMP1 pathways may have implications for the growth of both normal and transformed epithelial cells.

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Section: Discussionmentioning

confidence: 96%

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

et al. 1997

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“…This is supported by the ability of anti-IL-6 to suppress epidermal proliferation and epidermal thickness. Successful medical intervention can decrease IL-6 levels in psoriatic skin [33], and IL-6 can stimulate human keratinocyte proliferation in culture. The significant effect of anti-IL-6 treatments in the current study supports the notion that IL-6 may play a primary role in the epidermal hyperplasia of psoriasis.…”

Section: Discussionmentioning

confidence: 99%

In vivo effects of cytokines on psoriatic skin grafted on nude mice: involvement of the tumour necrosis factor (TNF) receptor

Gilhar

David

Kalish³

et al. 1996

Clinical and Experimental Immunology

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SUMMARYFollowing engraftment of human involved psoriatic skin to nude mice there is a partial normalization of pathology associated with a loss of inflammatory leucocytes. However, the epidermis remains hyperproliferative, which may reflect a primary defect. The roles of TNF-®, IL-1 and IL-6 in epidermal hyperproliferation of grafted psoriatic lesions were investigated. Before and after treatment, grafts were analysed to determine epidermal thickness and labelling index (LI). HLA-DR, intercellular adhesion molecule-1 (ICAM-1), and TNF receptor (TNF-R; p75 and p55) expression were determined by immunoperoxidase staining. Psoriatic epidermis was found consistently to be negative for p55 TNF-R and p75 TNF-R before grafting. Following engraftment, TNF-R-positive cells (i.e. p55 by keratinocytes; p75 by epidermal dendritic cells) were identified throughout the epidermis. Higher numbers of p75 TNF-R epidermal dendritic cells were found in grafts following a course of TNF-®, IL-6 or IL-1 treatment. The p55 form of the TNF-R expressed by keratinocytes was significantly elevated after treatment with TNF-® or IL-6. HLA-DR and ICAM-1 were also expressed in these grafts. TNF-®, anti-IL-1, and anti-IL-6 treatment induced a marked decrease in the epidermal thickness and LI of psoriatic graft tissue, correcting the hyperproliferation associated with psoriatic epidermis. Supraphysiological levels of TNF-® may saturate and consequently down-regulate their own receptors, leading to a paradoxical inhibitory effect.

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“…Enhanced angiogenesis and increased vascular permeability of synovial tissue are pathological features of RA, and these characteristics are due to the excess production of vascular endothelial growth factor (VEGF), which is induced by IL-6 in synovial fibroblasts [22]. The promotional activities of IL-6 such as the proliferation of keratinocytes or collagen production in dermal fibroblasts may contribute to autoimmune skin diseases such as psoriasis and systemic sclerosis, respectively [23,24].…”

Section: Interleukin-6mentioning

confidence: 99%

Anti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases

2011

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Interleukin (IL)‐6 is a cytokine with multiple biological activities. It contributes to host defense against pathogens, whereas accelerated production of IL‐6 plays a significant pathological role in various diseases. Clinical trials have demonstrated the efficacy of tocilizumab, a humanized anti‐IL‐6 receptor antibody, for patients with rheumatoid arthritis, Castleman's disease or juvenile idiopathic arthritis, leading to approval of this innovative drug for the treatment of these diseases. Since IL‐6 has been demonstrated to play a significant role in the development of various other autoimmune and inflammatory diseases, tocilizumab can be expected to become a novel drug for such diseases as well.

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Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes.

Abstract: Psoriasis is a common papulosquamous skin disease. The histopathology is characterized by epidermal hyperplasia and inflammation. Recent studies suggest that keratinocyte proliferation and inflammation in psoriasis are manifestations of the same underlying pathological process.

Cited by 783 publications

References 19 publications

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

In vivo effects of cytokines on psoriatic skin grafted on nude mice: involvement of the tumour necrosis factor (TNF) receptor

Anti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases

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