Suppression of the inflammatory cytokine IL-18 activity by controlling the receptor function

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Interleukin 18 (IL-18) is a cytokine that induces the production of interferon γ, acute hepatitis, rheumatism, self-immune reaction and so on. In order to suppress the inflammatory effect of IL-18, we searched the compounds that control the IL-18 activity.1. Search of antibodies that inhibit IL-18 binding to its receptorPeptides that cover all sequence of the outer cellular domain of IL-18 receptor were synthesized. Using the peptide, peptide conjugates with KHL hemocyanine and BSA were prepared and immunized. However, no antigen that inhibits IL-18 activity was obtained.2. Evaluation of characteristics of trans-membrane domains of IL-18 receptor in terms of interference of the signal transaction through the receptorIn order to know the effect of the segment corresponding to the trans-membrane domain of the receptor to the signal transaction into cell, several segments of the trans-membrane domain were synthesized. However, no segments were able to be dissolved by detergents.3. Search of phages that quench the function of IL-18 receptorPhagemid libraries were prepared by using pSKAN Phagemid Display System (MoBiTec). However, phages themselves induce the production of interferon γ production. Therefore, we could not estimate the effect of peptides displayed on the phages.4. Search of peptides that suppress the IL-18 activityIL-18 is predicted to have a similar 3D structure to that of IL-1β and the complex crystal structure of IL-1β and IL-1 receptor has been solved. Based on the date deduced from the 3D structure, we synthesized partial sequences of IL-18 and evaluated the effects on the inhibition of IL-18 activities. As results, peptide, IL-18(113-157) and a mixture of IL-18(113-157) and IL-18(46-66) strongly inhibit the production of IFN-γ by L-18 addition.In conclusion, the mixture of the partial sequences of IL-18 suppresses the IL-18 activity and this fact will present a solid basis for designing inhibitors against IL-18.