IL1 Family Members in Inflammatory Skin Disease

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Abstract. The cytokines IL-1a and IL-1| have long been known to play a profound role in inflammation, and in the past decade another cytokine, IL-18 (originally known as IGIF), has also been realized to be an IL-1 family member and to possess significant inflammatory activity. Half a dozen additional members of the IL-1 family have been identified in recent years, and given their relatedness to IL-1 and IL-18, it is tempting to speculate that they too might possess inflammatory potential. We have demonstrated that certain of these cy-tokines can activate MAP kinases and the pathway leading to NFkB, via known IL-1R family members. Moreover, when overexpressed in skin, they are capable of causing an inflammatory skin condition resembling that seen in human disease.

The cytokines IL-1 a and IL-1| have long been known to play a profound role in inflammation, acting on virtually every organ system and cell type in the body (Dinarello 2002) to induce other cytokines, chemokines, adhesion molecules, and mediators such as NO and prostaglandins. Nine years ago, a new cytokine, originally known as IGIF and now termed IL-18, was cloned and soon realized to be related by descent to IL-1 (Oka-

mura et al. 1995; Bazan et al. 1996). IL-18 also acts in pro-inflammatory fashion, primarily by its ability (under normal conditions) to promote expansion and differentiation of the Th1 helper T cell population and to induce the Th1 cytokine, interferon gamma (IFN-y). Since that time, the IL-1 family has continued to expand so that it is now comprised of ten members (Dunn et al. 2001; Sims et al. 2001). The grouping of these ten genes into a family is based on conservation of sequence, of three-dimensional structure, and of gene organization and location (Smith et al. 2000; Taylor et al. 2002; Nicklin et al. 2002; Dunn et al. 2003).

IL-1 exerts its activities by binding to the type I IL-1 receptor and subsequently recruiting a homologous molecule, the IL-1 receptor accessory protein (AcP) (Sims 2002). It is the heterodimeric receptor complex that is competent for signaling. IL-18 acts in similar fashion, binding to IL-18Ra and subsequently recruiting an accessory chain, IL-18RP, which initiates biological activities (Sims 2002). The polypeptides comprising both chains of the IL-1 and IL-18 receptor complexes are members of the IL-1 receptor family, which was originally defined by proteins comprised of three immunoglobulin domains in the extracellular portion, a single transmembrane domain, and a cytoplasmic portion, which contains a TIR (toll interleukin-1 receptor) domain. As the IL-1 ligand family has expanded, so has the IL-1 receptor family, to include nine members (Born et al. 2000). One of the newer members has only one Ig domain, and several have extra amino acids C-terminal to the TIR domain, but the essential family attributes remain.

The similarities between IL-1, IL-18, and their receptors, on the one hand, and the new IL-1 and IL-1R family members, on the other hand, readily leads to speculation that the latter may, like their previously characterized cousins, play roles in inflammation. Indeed, a report in 2001 (Debets) claimed that one of the new ligands, IL-1F9, was able to induce NFkB activity in Jurkat cells as long as the cells had been transfected with a formerly orphan IL-1R family member, IL-1R rp2. We were able to confirm this result, and extend it to demonstrate that not only IL-1F9, but also IL-1F6 and IL-1F8, possessed the ability to activate the pathway leading to NFkB (Towne et al. 2004). All three ligands do so not only in Jurkat cells, but in many human and mouse cell lines, as long as the cells express IL-1R rp2, and can induce activation of the MAP kinases Erk and JNK in addition to NFkB. Antibody-blocking and transfection experiments suggest that both AcP (the same AcP that plays a role in IL-1 signaling) and IL-1R rp2 are required for these responses. There are two unusual aspects to the activity of IL-1F6, F8, and F9, however, which remain unresolved. One is the high ligand concentration required for signaling. The cell lines assayed to date do not respond to these ligands at concentrations less than 10 ng/ml, and concentrations of 1-5 ug/ml are required in order to obtain a maximal response. Both of these values are several orders of magnitude higher than is seen with IL-1, for example, and about one order of magnitude higher than demonstrated by IL-18. Second, we have not been able to detect binding of IL-1F6, F8, or F9 to either IL-1R rp2 or AcP, by a variety of techniques including surface plasmon resonance. Whether these results suggest the existence of an additional receptor subunit, not expressed on our assay cell lines and not required for signaling but providing extra affinity for the ligand, or some other explanation, is not currently clear.

In vivo, IL-1a has been shown to be capable of inducing an inflammatory skin condition when expressed under control of the keratin-14 promoter at levels approximately ten times greater than that seen following the potent inflammatory stimulus LPS (Groves et al. 1995). However, when expressed constitutively at levels similar to those induced by LPS, which are still very high, the inflammatory skin phenotype is only occasionally seen. Skin-specific expression of IL-18 also results in an inflammatory condition, although one that is slow to develop (Konishi et al. 2002). Overexpression of IL-18 in the skin also exacerbates dermatitis elicited by irritants or contact hypersensitivity (Kawase et al. 2003). Interestingly, skin-specific expression of caspase 1, the protease responsible for cleaving the inactive precursors of both IL-18 and IL-1P to their active forms, leads to a chronic erosive dermatitis developing at about 8 weeks of age and persisting through the life of the animal (Yamanaka et al. 2000). Double-mutant animals transgenic for keratin14-expressed caspase 1 but deficient in IL-18 failed to develop the dermatitis. Double-mutant animals transgenic for keratin14-expressed caspase 1 but deficient in IL-1 did develop the dermatitis but with a delayed time course. These results suggest that the pathological process leading to dermatitis in the caspase-1 transgenic mice requires IL-18, and is accelerated by IL-1 (Konishi et al. 2002).

In order to determine the in vivo effects of the newer IL-1 family members, we generated transgenic mice expressing either IL-1F6, IL-1F8, or IL-1R rp2 from the keratin 14 promoter. This promoter drives expression predominantly in the basal epithelium of the skin, although there is also some expression in the thymus, tongue, and forestomach of the mouse. Mice overexpressing any of these three genes under control of the K14 promoter develop an inflammatory skin disease, which histologically bears some resemblance to human psoriatic skin. Consistent with this finding, IL-1F6 and F8 can be seen by in situ hybridization to be present at elevated levels in human psoriatic skin, compared to skin from nondiseased individuals. Future studies will explore further the role of the novel IL-1 family members in human dermatological disease.

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