Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis.

Ju, G; Labriola–Tompkins, Emily; Campen, Carolyn A.; Benjamin, William R.; Karas, Jennifer L.; Plocinski, J; Biondi, Denise; Kaffka, K L; Kilian, Patricia L.; Eisenberg, Stephen P.

doi:10.1073/pnas.88.7.2658

Cited by 62 publications

(42 citation statements)

References 33 publications

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“…Due to the conservation of the ligand-binding domains of sIL-1RAcP, this molecule may still share the receptor complex stabilizing function, thereby acting as an inhibitor of IL-1 signaling through formation of an IL-1 trap. This action of sIL-1RAcP could therefore be distinct from IL-1Ra-mediated inhibition of IL-1 signaling, since binding of IL-1Ra to the IL-1RI does not lead to recruitment of IL-1RAcP (4,37,38). In this study, we compared the effect of both inhibitors on CIA.…”

Section: Discussionmentioning

confidence: 99%

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Smeets¹,

Joosten²,

Arntz³

et al. 2005

Arthritis & Rheumatism

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Objective. To discern the mode of interleukin-1 (IL-1) inhibition of soluble IL-1 receptor accessory protein (sIL-1RAcP) by comparison with IL-1 receptor antagonist (IL-1Ra) in arthritis.Methods. Adenoviral vectors encoding either sIL1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Antibovine type II collagen IgG and IL-6 were quantified in serum. Proliferative response of splenic T cells was determined in the presence of sIL-1RAcP or IL-1Ra. The effect on IL-1 inhibition of recombinant sIL-1RAcP and IL-1Ra was further examined in vitro, using NF-B luciferase reporter cell lines. Quantitative polymerase chain reaction was used to determine the relative messenger RNA expression of the IL-1 receptors.Results. Adenoviral overexpression of both sIL1RAcP and IL-1Ra resulted in amelioration of the collagen-induced arthritis. Both IL-1 antagonists reduced the circulating levels of antigen-specific IgG2a antibodies, but only IL-1Ra was able to inhibit lymphocyte proliferation. By using purified lymphocyte populations derived from NF-B reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-B activity in B cells but not T cells, whereas IL-1Ra inhibited IL-1 on both cell types. A study in a panel of NF-B luciferase reporter cells showed that the sIL-1RAcP inhibits IL-1 signaling on cells expressing either low levels of membrane IL-1RAcP or high levels of IL-1RII.Conclusion. We show that the sIL-1RAcP ameliorated experimental arthritis without affecting T cell immunity, in contrast to IL-1Ra. Our results provide data in support of receptor competition by sIL-1RAcP as an explanation for the different mode of IL-1 antagonism in comparison with IL-1Ra.

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Section: Discussionmentioning

confidence: 99%

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Smeets¹,

Joosten²,

Arntz³

et al. 2005

Arthritis & Rheumatism

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“…2A). Changing it to lysine, as found in IL-1Ra (Lys 145 ), drastically reduces the agonistic activity of IL-1b, whereas the reverse mutation renders IL-1Ra partially agonistic (31,32). In the IL-1R complex structures, IL-1b residue Asp 145 makes a direct hydrogen bond to Ser 185 of IL-1RAcP (Supplemental Fig.…”

Section: Charge Effects On Binding To Il-1racp and Il-36r Signalingmentioning

confidence: 99%

“…In addition to the importance of the b4/5 and b11/12 loops, it has been reported that a charged residue directly C-terminal of the b11/12 loop has a large influence on the agonist and antagonistic properties of IL-1b relative to IL-1Ra (31). In IL-1b this residue is an aspartate (Asp 145 ) (Fig.…”

Section: Charge Effects On Binding To Il-1racp and Il-36r Signalingmentioning

confidence: 99%

Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Guenther

Sundberg

2014

The Journal of Immunology

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The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36γ, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1.

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“…The next step was to test the (51), in black and red, respectively). The asterisk indicates a residue, which together with the loop region between ␤4 and ␤5, is crucial in determining antagonist activity in IL-1ra (49,52). The amino acid coloring scheme depicts chemically similar residues: green (hydrophobic); red (acidic); blue (basic); yellow (C); orange (aromatic); black (structure breaking); and gray (tiny).…”

Section: Il-1␦ and Il-1⑀ Do Not Activate Nf-b Through Classical Il-1rsmentioning

confidence: 99%

Two Novel IL-1 Family Members, IL-1δ and IL-1ε, Function as an Antagonist and Agonist of NF-κB Activation Through the Orphan IL-1 Receptor-Related Protein 2

Debets

Timans

Homey

et al. 2001

The Journal of Immunology

242

224

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IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1δ and IL-1ε. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1δ and ε. Levels of keratinocyte IL-1δ are ∼10-fold higher than those of IL-1ε. In vitro stimulation of keratinocytes with IL-1β/TNF-α significantly up-regulates the expression of IL-1ε mRNA, and to a lesser extent of IL-1δ mRNA. In NF-κB-luciferase reporter assays, we demonstrated that IL-1δ and ε proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1α and β or IL-18. However, IL-1ε activates NF-κB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1δ, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1ε response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1δ and ε and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1αβ/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.

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Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis.

Abstract: Interleukin 1 (IL-1) receptor antagonist (IL-

Cited by 62 publications

References 33 publications

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Two Novel IL-1 Family Members, IL-1δ and IL-1ε, Function as an Antagonist and Agonist of NF-κB Activation Through the Orphan IL-1 Receptor-Related Protein 2

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