TPL2 regulates IL-1β production in response to TLR2 stimulation in human monocytes. (A) Pharmacologic TPL2 inhibition results in a dose-dependent decrease of IL-1β transcription in response to TLR2 stimulation of human monocytes. THP-1 cells were stimulated with a TLR2 agonist, Pam3CSK4, for 3 hours with or without pretreatment with a TPL2 kinase inhibitor as shown. RNA was extracted and subjected to RT-PCR using IL-1β–specific primers. Pam3CSK4 is thought to act predominantly through TLR2/TLR1 heterodimers, whereas a related lipopeptide, Pam2CSK4, acts through TLR2/6 heterodimers. Pharmacologic TPL2 inhibition resulted in dose-dependent decrease of mature IL-1β secretion into culture supernatants after stimulation by either Pam3CSK4 (B) or Pam2CSK4 (C). P values: *<.05, **<.01, ***<.001. Tpl2i, Tpl2 inhibitor. (D) Diagram summarizing the central role of the versican-TLR2/6-TPL2 pathway in regulating the inflammatory milieu of the myeloma niche. TLR2/6 heterodimers on MAM recognize versican cleaved by ADAMTS1 and/or unprocessed versican. Versican-induced TLR2/6 signaling activates TPL2 kinase and is essential for IL-1β and IL-6 induction in the myeloma niche.