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Selected Publication:
Singh, T.
The pathogenic significance of IL-23/Th17 axis, regulatory T cells, and platelet activating-factor (PAF) in the psoriatic phenotype of K5.hTGF-ß1 transgenic mice
[ Dissertation ] Medical University of Graz; 2010. pp. 89
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- Authors Med Uni Graz:
- Singh Tej Pratap
- Advisor:
- Heinemann Akos
- Wolf Peter
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- Abstract:
- The IL-23/Th17 and regulatory T cell (Treg) axis were studied in the pathogenesis of skin disease in K5.hTGF-ß1 transgenic mice, exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. An impaired function of CD4+CD25+ Tregs and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. These conclusions were mainly deduced from the interference with the pathogenesis of disease by (1) psoralen+UVA (PUVA) photochemotherapy, (2) anti-IL-17 antibody treatment, and (3) platelet-activating-factor (PAF) injection or blockade of its receptor. (1) K5.hTGF-ß1 transgenic mice were treated with PUVA, a standard dermatological therapy. It suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORgammat. PUVA induced the Th2 pathway and IL-10 producing CD4+CD25+Foxp3+Tregs (iTregs) with disease-suppressive activity that was abolished by anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin, which indicated that both iTregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA. (2) Anti-IL-17 antibody was used to neutralize the bioactivity of IL-17. Injecting anti-IL-17 mAB intraperitoneously into K5.hTGF-ß1 transgenic mice diminished the psoriatic phenotype of the mice. Treatment with anti-IL-17 mAb did not show any effect on FoxP3 and IL-10 mRNA expression in the skin of K5.hTGF-ß1 transgenic mice suggesting independent involvement of Treg and Th17 axis in psoriasis. (3) Injecting PAF into the skin of transgenic mice led to inflammation and accelerated the manifestation of the psoriatic phenotype by a local effect. In contrast, injecting mice intraperitoneously with PAF receptor antagonist PCA-4248 lowered the PAF level (most likely by depressing an autocrine loop). In addition PCA-4248 treatment also lowered neutrophil, CD68+ cell (monocyte/macrophage) and CD3+T cell accumulation in the skin and blocked progression of the psoriasis-like phenotype. This effect of PAF blockade was similar to that of PUVA and paralleled by a decrease of abnormally elevated mRNA and/or protein levels of Th17-related cytokines IL-17A, IL-17F, IL-23, IL-12A, and IL-6, and the transcription factor STAT3. In contrast, PCA-4248 treatment upregulated the mRNA levels of COX2 and IL-10 in the dorsal skin and release of IL-10 in the serum and skin. 4 These findings imply that specifically interfering with IL-23/Th17, Tregs and/or PAF may be an option to induce cytokine pathways with disease suppressive activity and develop novel anti-psoriatic therapeutic strategies in particular for hyper-inflammatory disease variants and associated systemic comorbidities.