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Tolerance Induced by the Lipopeptide Pam₃Cys Is Due to Ablation of IL-1R-Associated Kinase-1¹

Maciej Siedlar^*,, Marion Frankenberger, Elke Benkhart^*,, Terje Espevik, Martina Quirling^¶, Korbinian Brand^¶, Marek Zembala and Loems Ziegler-Heitbrock^2,,||

^* Institute for Immunology, University of Muenchen, Muenchen, Germany; Department of Clinical Immunology, Jagiellonian University Medical College, Kraków, Poland; Clinical Cooperation Group "Inflammatory Lung Diseases" (Institute for Inhalation Biology, GSF National Research Center and Asklepios Fachkliniken, München-Gauting), Gauting, Germany; Institute of Cancer Research and Molecular Biology, Medisinsk Teknisk Senter, Trondheim, Norway; ^¶ Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität, München, Germany; and ^|| Department of Microbiology and Immunology, University of Leicester, Leicester, United Kingdom

Stimulation of the human monocytic cell line Mono Mac 6 with the synthetic lipopeptide (S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys₄-OH, trihydrochloride (Pam₃Cys) at 10 µg/ml induces a rapid expression of the TNF gene in a TLR2-dependent fashion. Preculture of the cells with Pam₃Cys at 1 µg/ml leads to a reduced response after subsequent stimulation with Pam₃Cys at 10 µg/ml, indicating that the cells have become tolerant to Pam₃Cys. The CD14 and TLR2 expression is not decreased on the surface of the tolerant cells, but rather up-regulated. Analysis of the NF-B binding in Pam₃Cys-tolerant cells shows a failure to mobilize NF-B-p50p65 heterodimers, while NF-B-p50p50 homodimers remain unchanged. Pam₃Cys-tolerant cells showed neither IB-Ser³² phosphorylation nor IB degradation but MyD88 protein was unaltered. However, IRAK-1 protein was absent in Pam₃Cys-induced tolerance, while IRAK-1 mRNA was still detectable at 30% compared with untreated cells. In contrast, in LPS-tolerized cells, p50p50 homodimers were induced, IRAK-1 protein level was only partially decreased, and p50p65 mobilization remained intact. It is concluded that in Mono Mac 6 monocytic cells, inhibition of IRAK-1 expression at the mRNA and protein levels is the main TLR-2-dependent mechanism responsible for Pam₃Cys-induced tolerance, but not for TLR-4-dependent LPS-induced tolerance.

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