Human Keratinocytes Constitutively Express Interleukin-18 and Secrete Biologically Active Interleukin-18 After Treatment with Pro-Inflammatory Mediators and Dinitrochlorobenzene

Abstract

Interleukin-18 is a potent inducer of interferon-gamma by activated T cells, macrophages, and monocytes and is synthesized as an inactive precursor. Pro-interleukin-18 must be cleaved by interleukin-1-beta-converting enzyme for secretion of the biologically active form. We report that among selected non-bone marrow derived skin cells, interleukin-18 mRNA is constitutively expressed by human keratinocytes and not by dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes. Interleukin-18 mRNA and intracellular protein levels are neither changed in human keratinocytes nor induced in human dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes by exposure to pro-inflammatory stimuli. Exposure of human keratinocytes to phorbol 12-myrisate 13-acetate, lipopolysaccharides or the contact sensitizer DNCB results in the secretion of immunoprecipitable interleukin-18 protein. Human keratinocyte-secreted interleukin-18 is biologically active, in that conditioned media from phorbol 12-myrisate 13-acetate, lipopolysaccharide and DNCB-treated human keratinocytes induce interferon-gamma expression by peripheral blood mononuclear cells. This bioactivity is neutralized by anti-interleukin-18, but not anti-interleukin-12 antibodies. By immunohistochemistry, interleukin-18 protein is detected in basal keratinocytes of normal human skin, but its expression is markedly upregulated in suprabasal keratinocytes in psoriasis. These findings indicate that human keratinocytes are a source of biologically functional interleukin-18 and thus are capable of playing an initiating part in the local interferon-gamma-dependent inflammatory processes through expression, activation, and secretion of interleukin-18.

IL-18 Reduces Ultraviolet Radiation-Induced DNA Damage and Thereby Affects Photoimmunosuppression

“…IL-18 is secreted by a variety of cells including macrophages, dendritic cells, and epithelial cells (23). In particular, both human and murine keratinocytes have been demonstrated to be a source for IL-18 (42,43). Thus, it is fair to speculate whether constitutive secretion of IL-18 in the skin might represent an endogenous mechanism reducing the risk of photocarcinogenesis.…”

A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing

“…Interleukin (IL)-18, a member of the IL-1 superfamily, is a proinflammatory cytokine produced by a wide range of cells including monocytes/macrophages, T and B cells, dendritic cells and epithelial cells (Dinarello, 1999;Gardella et al, 1999Gardella et al, , 2000Naik et al, 1999). IL-18 shares some biological properties with IL-12 (Trinchieri, 2003), such as induction of interferon gamma (IFN g) secretion by T cells, enhancement of natural killer cell cytotoxicity and stimulation of Th1 cell differentiation (Okamura et al, 1995;Ushio et al, 1996;Kohno et al, 1997;Takeda et al, 1998).…”

Expression of interleukin‐18 in human ovarian carcinoma and normal ovarian epithelium: Evidence for defective processing in tumor cells

“…[1][2][3][4][5][6] This molecule is able to induce IFN-␥ and TNF-␣ production by T cells 5,6 and to stimulate NK cell cytotoxicity 7 and T-cell proliferation. 8,9 IL-18, like IL-1␤, is synthesized as an inactive precursor (pro-IL-18 24kDa), which is cleaved by interleukin-1␤-converting enzyme (ICE or caspase-1) into an active 18 KDa mature form and secreted.…”