In addition to RAGE, the Toll-like family of receptors has been demonstrated to be important in HMGB1 signaling. Members of the TLR family share many structural similarities, both extracellularly and intracellularly, but they differ from each other in ligand specificity, expression patterns, and, in some instances, the signaling pathways they activate. Generally, TLRs can recognize both DAMPs and PAMPs and hence are involved in immune response to both infection and injury. Members of the Toll family have specific ligands, and TLR4 might be the most well known and for its role in the bacterial endotoxin (LPS) recognition complex (60) . TLR4, TLR2, and TLR9 have all been implicated as HMGB1 receptors. HMGB1 binding of TLR2 and TLR4 results in NF-κB upregulation (61) (62) (63) , thus making it likely that HMGB1 stimulation of these receptors can lead to cytokine release. Interestingly, HMGB1-mediated TLR4 activation is different from that resulting from LPS stimulation (50, 62) . For example, when applied to cell cultures, HMGB1 activates both IKKα and IKKβ, whereas LPS only activates IKKβ. Additionally, the MAPK protein activation and cytokine production profiles differ between HMGB1-and LPS-treated cells.