Interleukin-1 Receptor Antagonist Suppresses Contact Hypersensitivity

Abstract

Interleukin-1 receptor antagonist (IL-1ra), a naturally occurring inhibitor of interleukin-1 (IL-1), blocks IL-1 binding to its receptors but has no agonistic activity. IL-1 is thought to play an important role in contact hypersensitivity (CHS), although the effects of exogenously administered IL-1 in CHS have been somewhat controversial. To clarify the role of IL-1 in CHS, we studied the effect of IL-1 receptor blockade using exogenous IL-1ra and evaluated these effects on CHS. We examined the in vivo effects of local administration of recombinant human IL-1ra in the murine CHS model. Local injection of IL-1ra to sensitized BALB/c mice just before challenge with dinitrofluorobenzene resulted in a significant reduction in the intensity of CHS responses, assessed by ear swelling. A dose-response study revealed that maximal inhibition of ear swelling (36% to 43%) was observed after intradermal injection of IL-1ra at doses of 10 to 100 micrograms/ear. This reduction in ear swelling in IL-1ra-injected ears consisted of less inflammatory cell infiltration and decreased edema in the dermis compared with controls. Suppression of CHS was observed when IL-1ra was applied in the 24-h interval preceding challenge with dinitrofluorobenzene, whereas no suppressive effect was observed when IL-1ra was applied 48 h before or after the challenge. Local administration of IL-1ra to naive mice 5 h before sensitization also suppressed CHS responses. However, IL-1ra injection did not suppress phenol-induced inflammation. These results suggest that IL-1ra is an effective inhibitor of both the sensitization and elicitation phases of CHS expression in mice, thus emphasizing the role of IL-1 as an immunologic potentiator of responses associated with CHS.

Development of a Novel Noncompetitive Antagonist of IL-1 Receptor

“…1) and exhibits properties consistent with those of an allosteric negative modulator. As a competitive inhibitor of IL-1, IL-1ra interferes with all actions of IL-1RI, including desirable ones related to innate immunity, and hence increases the risk of cancer and seemingly of infections (85). In this report, we have described the first small molecule (peptide) antagonist of a cytokine receptor, notably of IL-1RI, which seems to integrate allosteric modulatory properties; 101.10 is specific, potent and effective in vitro and in vivo in (IL-1-implicated) models of inflammation after systemic and topical applications.…”

Roles of TNF-α and IgE in the late phase of contact hypersensitivity induced by trimellitic anhydride

“…Histological examination has also revealed the infiltration of basophils and eosinophils in the superficial dermis as the characteristics of the animal skin reaction (Sugawara et al, 1993). Studies have demonstrated that the local release of cytokines, including TNF-α, IL-1, and IFN-γ, is critical for the optimal generation of the CHS and that TNF-α is believed to play a role in the pathogenesis of asthma in humans and asthma and CHS in animal models (Piguet et al, 1991;Kondo et al, 1995;Wang et al, 2003). TNF-α, which is recognized as a powerful mediator of inflammatory reaction, might induce these alterations either directly, since it can react with a wide range of cell types (Beutler and Cerami, 1989), or indirectly by the activation of several other cells.…”

“…Studies have demonstrated that local release of cytokines, including TNF-α, IL-1, and IFN-γ, is critical for the generation of the CHS reaction (Piguet et al, 1991;Kondo et al, 1995;Wang et al, 2003). TNF-α is a pleiotropic cytokine involved in host defense mechanisms and inflammatory responses (Vassalli, 1992;Shah et al, 1995).…”

The Role of NK Cells in the Elicitation Phase of Oxazolone Inducing Contact Hypersensitivity

“…Recent studies of CHS found that pro-inflammatory effects such as the induction of TNF-a, IFN-g, IL-1 secretion [10,16,23,24] and expression of ICAM-1, VCAM-1, ELAM-1 [7,28] constitute an important process for the elicitation phase of CHS. Since these pro-inflammatory effects of haptens are non-immunological in nature, they do not require Ag-specific recognition.…”

“…The roles of Langerhans cells (LCs), antigen (Ag) recognition of T and B cells, cytokine synthesis, and cell adhesion molecules have also been analyzed [1,4,5,7,10,15,16,23,24,27,28]. T cell clones derived from peripheral blood and dermal tissues of CHS patients and mice were studied, and most of these phenotypes have been found to possess CD4 + [20].…”