IL‐38 orchestrates proliferation and differentiation in human keratinocytes

Abstract

Interleukin (IL)-38 is a member of the IL-1 cytokine family with reported antiinflammatory activity. The highest constitutive IL-38 expression is detected in the skin, where it is mainly produced by differentiating keratinocytes. However, little data are available regarding its biological functions. In this study, we investigated the role of IL-38 in skin physiology. We demonstrate here that dermal fibroblasts and epithelial cells of skin appendages, such as eccrine sweat glands and sebaceous glands, also express IL-38. Next, using two-and three-dimensional cell cultures, we show that endogenous expression of IL-38 correlates with keratinocyte differentiation and its ectopic overexpression inhibits keratinocyte proliferation and enhances differentiation. Accordingly, immunohistochemical analysis revealed downregulation of IL-38 in skin pathologies characterized by keratinocyte hyperproliferation, such as psoriasis and basal or squamous cell carcinoma. Finally, intracellular IL-38 can shuttle between the nucleus and the cytoplasm and its overexpression modulates the activity of the transcription regulators YAP and ID1. Our results indicate that IL-38 can act independently from immune system activation and suggest that it may affect the epidermis directly by decreasing proliferation and promoting differentiation of keratinocytes. These data suggest an important role of keratinocyte-derived IL-38 in skin homeostasis and pathologies characterized by epidermal alterations.

Cell Intrinsic IL-38 Affects B Cell Differentiation and Antibody Production

“…As previously mentioned, tonsillar proliferative B cells were described to express IL-38 [ 1 ]. Moreover, we previously obtained indications for an intracellular role of IL-38 in different cell types [ 3 , 9 ]. When investigating the expression of IL-38 at the mRNA level during B cell differentiation from day 0 to day 10 using RT-qPCR, we observed a significant induction of IL1F10 mRNA encoding IL-38 at day 4, followed by a decrease at day 10 ( Figure 5 A).…”

“…Other members of the IL-1 family have already been described to have intracellular function on immune cells, such as IL-1α, IL-33, and IL-37 [ 34 , 35 , 36 ]. IL-38 was found to accumulate intracellularly not only in several cell types, including B cells and tonsil epithelia, but also in keratinocytes and macrophages [ 3 , 9 , 37 ]. It remains to be determined how intracellular IL-38 affects B cell differentiation.…”

“…However, IL-38 has also been associated with non-immunological processes, such as the control of keratinocyte differentiation. To that end, IL-38 may not only act through its putative receptors, since high levels of IL-38 are found in the cytoplasm of keratinocytes [ 2 , 3 , 4 ]. Concerning inflammatory signaling, an initial study in 2012 proposed IL-38 as an anti-inflammatory mediator, based on its capacity to dampen Th17 responses triggered by C. albicans .…”

“…IL-38 is constitutively expressed in the skin, predominantly in the epidermis, as well as in some lymphoid organs, where it is found particularly in B cells and macrophages [ 1 , 2 , 3 , 8 , 9 ]. In fact, the first study describing IL-38 found IL-38 expression in proliferating B cells in tonsils [ 1 ].…”

Recent advances in the role of Yes‐associated protein in dermatosis

“…IL‐17α was shown to promote the development of psoriasis via activation of the YAP/AREG axis 34 . Meanwhile, IL‐38 inhibited the transcriptional activity of YAP to suppress keratinocyte proliferation 35 . Inhibiting YAP expression improved skin lesions by inducing cell cycle arrest in G0/G1 phase and reducing the levels of inflammatory factors as well as activation of extracellular signal‐regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B signaling 36 .…”