Anti-IL-31 receptor antibody is shown to be a potential therapeutic option for treating itch and dermatitis in mice.

BACKGROUND AND PURPOSE: IL-31, which is described as a pruritogenic cytokine, is linked to the itching that is associated with allergic and non-allergic eczema, but the precise pruritogenic mechanism of IL-31 and its potential as a therapeutic target for atopic dermatitis (AD) have not been determined. EXPERIMENTAL APPROACH: We investigated the effects of existing drugs on the scratching behaviour induced by an i.v. injection of IL-31 to clarify whether IL-31 induced pruritus indirectly. In addition, we studied the effects of an anti-IL-31 receptor α subunit (anti-IL-31 receptor α) neutralizing antibody on chronic pruritus-inducing dermatitis in an AD-like model to determine whether IL-31 not only induces scratching behaviour, but is also the causative factor in an AD phenotype. KEY RESULTS: The scratching behaviour induced by an i.v. injection of IL-31 was inhibited by pretreatment with an anti-IL-31 receptor α-neutralizing antibody. In contrast, it was not inhibited significantly by a non-sedative antihistamine (terfenadine), immunosuppressants (dexamethasone and tacrolimus), or a µ-opioid receptor antagonist (naloxone). The anti-IL-31 receptor α-neutralizing antibody reduced the ear swelling and dermatitis score in a chronic pruritus-inducing AD-like model. Moreover, treatment with the anti-IL-31 receptor α-neutralizing antibody showed therapeutic effects on the dermatitis even if it was injected after the disease had developed. CONCLUSIONS AND IMPLICATIONS: Anti-IL-31 receptor α is a potential novel therapeutic approach for escaping from the itch-scratch cycle and also a treatment for dermatitis in AD.

Requirement for cooperative interaction of interleukin-6 responsive element type 2 and glucocorticoid responsive element in the synergistic activation of mouse metallothionein-I gene by interleukin-6 and glucocorticoid.

Metallothionein (MT)-inducing activity of interleukin (IL)-6 depends on the presence of glucocorticoid in hepatic cells. The synergistic action of IL-6 and glucocorticoid was observed in the transcriptional activation of the mouse MT (mMT)-I gene. We found that a 281-bp promoter was sufficient for IL-6 and glucocorticoid stimulation. Our inspection of this region revealed the putative type 1 and 2 IL-6 responsive elements (REs). Functional analyses of these regions were performed using luciferase reporter constructs, and it was observed that the type 2 IL-6RE exerted the major response to the IL-6 signal. The transcriptional factor binding to type 1 IL-6RE, nuclear factor-IL-6, hardly contributed to the activation of the mMT-I promoter by IL-6 and glucocorticoid. A glucocorticoid responsive element (GRE) was also required for the synergistic activation by IL-6 and glucocorticoid. Interestingly, this synergism was not observed when the type 2 IL-6RE and the GRE were kept apart. Therefore, the synergistic activation of the mMT-I gene by IL-6 and glucocorticoid may require not only that signal transducers and activators 3 (Stat3) and the glucocorticoid receptor (GR) bind to their respective responsive elements, but also that Stat3 and the GR physically interact with one another.

Blocking effect of anti-mouse interleukin-6 monoclonal antibody and glucocorticoid receptor antagonist, RU38486, on metallothionein-inducing activity of serum from lipopolysaccharide-treated mice.

Although there is much evidence to suggest that lipopolysaccharide (LPS)-induced elevation of hepatic metallothionein (MT) contents is mediated by cytokines, the presence of MT-inducing activity in the serum of LPS-treated animals has not been examined. It was found that serum from LPS-treated mice stimulated MT induction in a hepatoma cell culture. The MT-inducing activity in serum was highest 2 h after LPS injection. Tumor necrosis factor and interleukin (IL)-6 levels in the serum were highest 1 and 2 h, respectively, after LPS injection. Anti-mouse IL-6 monoclonal antibody neutralized MT-inducing activity in serum obtained from mice 2 h after LPS injection. The MT-inducing activity in serum was blocked by the glucocorticoid antagonist, RU38486. A similar requirement for glucocorticoid was also observed in an IL-6-stimulated culture. These results show that the LPS-induced elevation of hepatic MT is mediated by IL-6, and the expression of the stimulating activity of IL-6 is dependent on the presence of glucocorticoid.