Pam3CSK4 (Synonyms: Pam3Cys-Ser-(Lys)4)

Pam3CSK4 (Pam3CysSerLys4) is a synthetic triacylated lipopeptide (LP) and a TLR2/TLR1 ligand agonist with an EC50 of 0.47 ng/mL^[10]. Pam3CSK4 mimics the acylated amino terminus of bacterial LPs. Bacterial LPs are a family of pro-inflammatory cell wall components found in both Gram-positive and Gram-negative bacteria. These bacterial LPs are recognized by TLR2, a receptor that plays a pivotal role in detecting a diverse range of pathogen-associated molecular patterns (PAMPs).Recognition of Pam3CSK4, a triacylated LP, is mediated by TLR2 which cooperates with TLR1 through their cytoplasmic domain to induce the signaling cascade leading to the activation of NF-κB ^[1].

In HepaRG cells, Pam3CSK4 shows a broad antiviral activity against HBV. Pam3CSK4 is a well-characterized and specific TLR1/2 ligand^[2]. The anti-HBV effect of Pam4CSK4 is dependent on TLR1/2 and its adaptor MyD88, targeting TLR1 or TLR6 with specific siRNA do affect the feed-forward expression of TLR2 in the context of Pam3CSK4 activation ; but invalidation of TLR1 led to a reduced inhibitory effect of Pam3CSK4. The low functional level of TLR2 was sufficient to produce the therapeutic effect of Pam3CSK4^[4,5].Thus confirming that Pam3CSK4 likely signals through TLR1/2 heterodimers in hepatocytes^[3].

Activation of TLR2/1 heterodimers by Pam3CSK4 mediates pain and itching, whereas activation of TLR2/6 heterodimers by lipoteichoic acid (LTA) or yeast glycan leads to itching^[9]. As a cutaneous regulator, IL-13 activates sensory neurons and participates in the initiation of AD and itch^[7]. IL-13 alone did not lead to a significant increase in scratching number，TLR2 promotes IL-13 signaling in sensory neurons. Innate TLR2 signaling not only promotes itch and pain but convert transient TH2 cell-mediated dermatitis into persistent inflammation which is linked to chronic human AD^[8]. In mice pretreated with Pam3CSK4, IL-13 injection caused approximately twice as many scratches as vehicle injection^[6]. Pam3CSK4 enhances IL-13-induced calcium transient in sensory neurons and elevates IL-13-induced Itch-like behaviours in mice.

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[8]: Liu T, Gao YJ, et,al. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012 Apr;28(2):131-44. doi: 10.1007/s12264-012-1219-5. PMID: 22466124; PMCID: PMC3347759.
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[10]:Irvine KL, Hopkins LJ, Gangloff M, Bryant CE. The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6. Vet Res. 2013 Jul 4;44(1):50. doi: 10.1186/1297-9716-44-50. PMID: 23826682; PMCID: PMC3716717.