MyD88 blockade accelerates malignant transformation and stromal inflammation. (A) Mice were treated with LPS and MyD88 inhibitory peptide (MyD88i) or control peptide. At 6 h, pancreata were assayed for expression of IRAK and p-IRAK. (B–D) p48Cre;Kras^G12D mice were treated with caerulein for 2 d to accelerate carcinogenesis before sacrifice 3 wk later. In addition, mice were administered either MyD88 inhibitory peptide or control peptide. (B) Tumor size was recorded. (C and D) Paraffin-embedded pancreatic sections were stained using H&E and Ki67 and using mAbs directed against p53 (C) and CK19 (D) an epithelial cell marker (n = 6 mice/group). (E and F) WT chimeric and MyD88^−/− chimeric p48Cre;Kras^G12D mice were treated with caerulein and sacrificed at 3 wk. The fraction of metaplastic ducts and PanIN lesions was quantified (n = 4–6 mice/group; ***, P < 0.001). (G) Kras^G12D PDECs were cultured with MyD88 inhibitory peptide or control peptide. Cells were pulsed with [³H]thymidine for 20 h, and its incorporation was measured. (H and I) MyD88^−/− and WT mice were challenged with caerulein alone or caerulein + TRIF inhibitor or control peptide for 3 wk. Fibroinflammatory changes were quantified (n = 4–6 mice/group; ***, P < 0.001). Error bars indicate standard error of the mean.