RAGE-dependent and -independent mechanism of HMGB1-mediated events and the inhibitory effects of TM and TM-derived peptides. (A and B) Skin inflammation was induced in the mouse ear using UV irradiation. C57/BL6 mice (RAGE^+/+; white bars) received rhs-TM alone, sRAGE alone, or TM-derived peptides (each at 100 nmol/kg; i.p.) combined with sRAGE (25 nmol/kg; i.p.) at 1 hour and 12 hours after exposure to UV irradiation (n = 8 per group). RAGE-null mice (C57BL/6 strain; black bars) were UV irradiated and were treated with sRAGE (25 nmol/kg), rhs-TM, or TM-derived peptides (each at 100 nmol/kg; i.p.). After 3 days, ear swelling (A) and infiltrating leukocytes (B) were assessed. *P < 0.05 and **P < 0.01, compared with UV-irradiated, PBS-treated controls. ^#P < 0.05 and ^##P < 0.01, compared with UV-irradiated RAGE-null mice. (C and D) Mice (wild-type C57BL/6 and RAGE-null on the C57BL/6 background) received LPS (10 mg/kg; i.p.) alone or in the presence of TM, P-D1, P-D2+3, and PBS. (C) Effect of rhs-TM or TM-derived peptides on LPS-induced lethality. Mice received 3 i.p. doses (100 nmol/kg/mouse) of anti-HMGB1 or control IgY at 2, 12, and 24 hours after LPS challenge. (D) Mice were treated with LPS and also received either anti-HMGB1 IgY or nonimmune IgY (3 i.p. doses of 2 mg/kg/mouse of IgY at 2, 12, and 24 hours after LPS). In C and D, (–/–) indicates that RAGE-null mice were used, and (+/+) indicates that strain-matched controls were used.