Featured herein are non-naturally occurring cytokine domains that can be used, inter alia, to modulate cellular signalling responsive to interleukin-1 receptor I (IL-1 RI), to treat disorders, and to detect and/or bind to cellular receptors, as well as other agents. Exemplary cytokine domains can contain amino acid residues from at least two parental cytokines domains, for example, receptor binding features, surface features, β strands, and loops from at least two parental cytokines domains.