TSLP Expression: Cellular Sources, Triggers, and Regulatory Mechanisms

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine initially identified in the culture supernatant of a thymic stromal cell line. Highly expressed in the epidermis in skin lesions of atopic dermatitis patients, TSLP was subsequently found to be a critical factor linking responses at interfaces between the body and environment (skin, airway, gut, ocular tissues, and so on) to Th2 responses. Recent studies have revealed that various cell types other than epithelial cells and epidermal keratinocytes (such as mast cells, airway smooth muscle cells, fibroblasts, dendritic cells, trophoblasts, and cancer or cancer-associated cells) also express TSLP. Environmental factors such as Toll-like receptor ligands, a Nod2 ligand, viruses, microbes, allergen sources, helminths, diesel exhaust, cigarette smoke, and chemicals trigger TSLP production. Proinflammatory cytokines, Th2-related cytokines, and IgE also induce or enhance TSLP production, indicating cycles of amplification. Skin barrier injury, increased epidermal endogenous protease activity, and less epidermal Notch signaling, all of which have been reported in atopic dermatitis, and keratinocyte-specific loss of retinoid X receptors and treatment of skin with agonists for vitamin D receptor in mice induce TSLP production, Th2 response, or atopic dermatitis-like inflammation. The transcription factors NF-κB and AP-1, nuclear receptors, single nucleotide polymorphisms, microRNAs, and the peptidyl-proryl isomerase Pin1 regulate TSLP mRNA expression transcriptionally or posttranscriptionally. This review focuses on events upstream of TSLP production, which is critical in allergic diseases and important in other TSLP-related disorders i.e. production sites, cellular sources, environmental and endogenous triggers and regulatory factors, and regulatory mechanisms of gene expression.