Tpl2 contributes to IL-1β-induced IL-8 expression via ERK1/2 activation in canine dermal fibroblasts

Abstract

In autoimmune diseases, fibroblasts produce and secrete various cytokines and act as sentinel immune cells during inflammatory states. However, the contribution of sentinel immune cells (i.e. dermal fibroblasts) in autoimmune diseases of the skin, such as atopic dermatitis, has been obscure. The pro-inflammatory cytokine interleukin 1β (IL-1β) induces the expression of chemokines, such as interleukin 8 (IL-8), in autoimmune diseases of the skin. IL-8 induces the activation and recruitment of innate immune cells such as neutrophils to the site of inflammation. IL-1β-mediated induction of IL-8 expression is important for the pathogenesis of autoimmune diseases; however, the intracellular singling remains to be understood. To elucidate the mechanism of the onset of autoimmune diseases, we established a model for IL-1β-induced dermatitis and investigated MAPK signaling pathways in IL-1β-induced IL-8 expression. We also identified that a MAP3K Tpl2 acts as an upstream modulator of IL-1β-induced ERK1/2 activation in dermal fibroblasts. We observed an increase in the expression of IL-8 mRNA and protein in cells treated with IL-1β. ERK1/2 inhibitors significantly reduced IL-1β-induced IL-8 expression, whereas the inhibitor for p38 MAPK or JNK had no effect. IL-1β induced ERK1/2 phosphorylation, which was attenuated in the presence of an ERK1/2 inhibitor. IL-1β failed to induce IL-8 expression in cells transfected with siRNA for ERK1, or ERK2. Notably, a Tpl2 inhibitor reduced IL-1β-induced IL-8 expression and ERK1/2 phosphorylation. We confirmed that the silencing of Tpl2 in siRNA-transfected fibroblasts prevented both in IL-1β-induced IL-8 expression and ERK1/2 phosphorylation. Taken together, our data indicate the importance of Tpl2 in the modulation of ERK1/2 signaling involved in the IL-1β-induced development of autoimmune diseases affecting the dermal tissue, such as atopic dermatitis.

Snail Mucus Filtrate Reduces Inflammation in Canine Progenitor Epidermal Keratinocytes (CPEK)

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Mechanism and application of β‐adrenoceptor blockers in soft tissue wound healing

“…After damage, reepithelialization is required to restore the tissue barrier, which is achieved based on the proliferation and targeted migration of keratinocytes to the center of the wound 15 . Nearly 12 h after the wounding, keratinocytes at the wound edge receive signals from cytokines, growth factors and chemokines produced by platelets and inflammatory cells in the previous phase, detach cell−cell and cell−matrix adhesion, recombinant actin cytoskeleton structure to produce cytoplasmic extension, like Lamellipodium, and migrate along the matrix toward the wound bed 47 . This step requires MMPs to cut the connection between integrins on the cell membrane surface and the matrix to enable cells to mobilize across the matrix 48 .…”

Post-Translational Modifications in Atopic Dermatitis: Current Research and Clinical Relevance

“…MAPKs play facilitatory roles in the susceptibility to inflammation, which could activate the TNF-α signaling cascades and energize the NF-κB signaling pathways ( Giridharan and Srinivasan, 2018 ); in turn, inflammatory cytokines could promote MAPK phosphorylation and aggravate the secretion of those mediators in AD development ( Hong et al, 2015 ; Ryu et al, 2015 ; Noh et al, 2016 ; Pinto et al, 2018 ; Naruke et al, 2021 ; Ogura et al, 2021 ). Specifically, higher FcεRI (a receptor of IgE, can be upregulated by p38 phosphorylation) is detected in peripheral blood monocytes of AD patients compared with normal individuals, which increases the susceptibility of microbial antigens and allergens ( Song et al, 2015 ).…”