The invention represents the TLR/IL-1R signaling pathway inhibitory fusion polypeptide comprising TIR and dimerization domain which is composed of TIR domain and dimerization domain wherein TIR domain and dimerization domain are connected by a linker peptide and wherein the polypeptide optionally also contains a segment enabling plasma membrane localization. Addition of the dimerization domain to the TIR domain significantly improves the inhibitory potency of TIR domain. The invention also represents the application of the nucleic acid encoding fusion polypeptide comprising TIR and dimerization domain or the application of the recombinantly produced fusion polypeptide comprising TIR and dimerization domain, especially of the polypeptide additionally containing protein transduction domain, for the inhibition of cellular TLR/IL-IR signaling or for the manufacturing a drug used for the treatment of chronic or acute inflammatory conditions, such as infectious and autoimmune diseases, sepsis, septic shock, cancer and others resulting from improper and/or excessive TLR/IL-IR signaling.
