Imiquimod-Induced Interleukin-1α Stimulation Improves Barrier Homeostasis in Aged Murine Epidermis

Abstract

In response to acute disruption of the permeability barrier of aged mammals there is a diminished capacity for barrier recovery, analogous to other aged organs when stressed. Acute barrier disruption increases levels of epidermal cytokines, and cytokines are known regulators of keratinocyte mitogenesis, as well as lipid synthesis in extracutaneous tissues. Underlying the sluggish barrier recovery in aged skin are diminished mRNA and protein levels for the interleukin-1 cytokine family, and its receptors. To further elucidate the role of the interleukin-1 family of cytokines in the barrier repair response, cytokine production was stimulated in aged murine skin with topical imiquimod application. Imiquimod accelerated barrier recovery after acute insults to aged and young skin. These functional results correlated temporally with increased interleukin-1 alpha production in the epidermis following topical imiquimod administration to murine skin. Furthermore, intracutaneous injections of interleukin-1 alpha accelerated barrier recovery in aged mice. Finally, we showed that interleukin-1 alpha added to cultured human keratinocytes stimulates epidermal lipid synthesis. These studies provide further evidence for the role of reduced interleukin-1 alpha signaling in the decline of permeability barrier function in aged skin, and point to the potential use of cytokine augmentation in barrier dysfunction of the aged.

TLR7 and TLR8 as targets in cancer therapy

“…The latter activity is exemplified by IFNg-dependent downregulation of IgE-synthesis by resiquimod (Frotscher et al, 2002). Other indirect biological effects that can be explained by the TLR-dependent activation of NF-kB by imiquimod and subsequent expression of IFNa, IL-1 and other mediators include enhanced expression of the opioid growth factor receptor on tumor cells and cells of the inflammatory infiltrate (Urosevic et al, 2004) as well as changes in the epidermal barrier function (Barland et al, 2004).…”

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

“…Expression levels are elevated in the saliva of oral cancer patients, and high serum IL8 levels correlate with a poor clinical outcome in OSCC (41,42). The interleukin encoded by the IL1A gene is a potent mediator of inflammation and is involved in epidermal barrier function (43). Expression of IL1A can trigger inflammation leading to tumor formation in differentiated epidermal cells (44).…”

Intrinsic and extrinsic factors in skin ageing: a review

“…Intrinsic changes occur in all skin as people age, including decreased turnover, chemical clearance, thickness and cellularity, thermoregulation, mechanical protection, immune responsiveness, sensory perception, sweat and sebum production and vascular reactivity [21,49]. These changes represent a generalized atrophy with few structural alterations up to the age of 50, followed by slow deterioration [44].…”

“…Photoageing is the superposition of this solar damage on the normal ageing process, defined specifically by damage produced in tissue by single or repeated exposure to UV light, believed to account for the vast majority of not only aesthetic effects of skin ageing, but also clinical problems as well [21,49]. Modern Western culture has promoted tanned skin as healthy, resulting in steadily increasing rates of skin cancer and prematurely aged skin [21,41].…”