An isolated protein that comprises a chimeric interleukin-1 (IL-1) family cytokine domain of 148-160 amino acids in length, wherein the chimeric cytokine domain comprises 5, 6 or 7 segments having at least 80% amino acid identity to corresponding segments of a parental IL-1 family cytokine domain selected from human IL-1Ra (SEQ ID NO:3) and human IL-1β (SEQ ID NO: 1), and wherein adjacent segments are from different parental IL-1 family cytokine domains, wherein (i) at least residues 11-41 and 120-147 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1Ra (SEQ ID NO:3); and a. at least residues 1-6, 45-61 and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); or b. at least residues 1-8, 42-120, and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); wherein the isolated protein binds to IL-1 receptor I (IL-1RI) and antagonizes IL-1RI receptor signaling activity, and wherein the corresponding segments and corresponding residues are as indicated by the alignment provided in Figure 4. wherein the chimeric cytokine domain comprises 5, 6 or 7 segments having at least 80% amino acid identity to corresponding segments of a parental IL-1 family cytokine domain selected from human IL-1Ra (SEQ ID NO:3) and human IL-1β (SEQ ID NO: 1), and wherein adjacent segments are from different parental IL-1 family cytokine domains, wherein (i) at least residues 11-41 and 120-147 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1Ra (SEQ ID NO:3); and a. at least residues 1-6, 45-61 and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); or b. at least residues 1-8, 42-120, and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); (i) at least residues 11-41 and 120-147 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1Ra (SEQ ID NO:3); and a. at least residues 1-6, 45-61 and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); or b. at least residues 1-8, 42-120, and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); a. at least residues 1-6, 45-61 and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); or b. at least residues 1-8, 42-120, and 148-153 (according to IL-1β (SEQ ID NO: 1) numbering) are collectively at least 90% identical to corresponding residues of IL-1β (SEQ ID NO: 1); wherein the isolated protein binds to IL-1 receptor I (IL-1RI) and antagonizes IL-1RI receptor signaling activity, and wherein the corresponding segments and corresponding residues are as indicated by the alignment provided in Figure 4.