Counter-Regulation of Interleukin-1α (IL-1α) and IL-1 Receptor Antagonist in Murine Keratinocytes

Abstract

Interleukin-1alpha (IL-1alpha) is a potent proinflammatory cytokine constitutively expressed by keratinocytes, which also synthesize a specific inhibitor of IL-1 activity, intracellular IL-1 receptor antagonist (IL-1ra). Although homeostatic regulation of the IL-1 system in keratinocytes has long been suspected, there is currently little evidence for this. To explore this issue, the PAM212 murine keratinocyte cell line was exposed to increasing concentrations of either IL-1alpha or IL-1ra and the opposing ligand was assessed by ELISA. Release of IL-1ra was induced following stimulation by murine IL-1alpha in a concentration-dependent manner and, conversely, IL-1ra stimulation increased IL-1alpha release. To determine whether a similar homeostatic circuit operates in vivo, epidermis from transgenic mice in which overexpression of IL-1alpha or IL-1ra was targeted to keratinocytes was analyzed. Epidermal sheets derived from IL-1alpha transgenic mice released eight times more IL-1ra than those from wild-type mice following ex vivo culture and similarly, IL-1alpha release was increased 3-4-fold in epidermal sheets derived from IL-1ra transgenic epidermis, Use of specific neutralizing antibodies against type I and type II IL-1 receptors indicated that the counter-regulation mechanism is mediated extracellularly through the type I IL-1 receptor alone. Taken together, these observations provide the first demonstration of mutual counter-regulation of IL-1 receptor ligands in keratinocytes.

The Psoriatic Transcriptome Closely Resembles That Induced by Interleukin-1 in Cultured Keratinocytes

“…The relatively small number of transcripts induced by IL-1␣, compared with IFN-␥, may reflect the recently described homeostatic control of IL-1 in murine epidermis, in which a small amount of IL-1␣ is constitutively released by keratinocytes, and excess IL-1 results in a type I IL-1 receptor-dependent up-regulation of IL-1ra release. 29 Consistent with this, a previous study observed an unexpectedly small number of transcripts regulated in ovarian epithelial cells following exposure to IL-1␣. 30 In addition to those molecules common to the psoriatic lesional transcriptome, a number of genes with broadly opposing roles were induced by IL-1␣.…”

Development of Transgenic Cloned Pig Models of Skin Inflammation by DNA Transposon-Directed Ectopic Expression of Human β1 and α2 Integrin

“…Secreted IL-1α contributes to keratinocyte hyperproliferation by EGFR-dependent activation of the Erk/MAPK pathway and has been shown to induce inflammatory conditions in mouse and human epidermis [72], [73]. Under normal conditions the activity of IL-1α is tightly regulated [74] by mechanisms that do not depend on ECM-induced integrin ligation [49]. However, there are numerous examples of signal co-operativity between integrins and IL receptors, suggesting that integrins may assist in intensifying cytokine signaling [75], [76].…”

Epidermal Receptor Activator of NF-κB Ligand Controls Langerhans Cells Numbers and Proliferation

“…This paradox may be explained by the supposition that the consequences of RANKL over-activity are carefully controlled in the epidermal microenvironment, either by regulation of cell surface expression of RANK, by increased production of OPG, or by changes in downstream signaling pathways. Moreover, we have recently shown that in other K14 transgenic mice, there is complex regulation of the consequences of transgene-driven secreted cytokine release (32).…”