Endogenous secretory leukocyte protease inhibitor inhibits microbial‐induced monocyte activation

In the intestine, epithelial factors condition incoming immune cells including monocytes to adapt their threshold of activation and prevent undesired inflammation. Colonic epithelial cells express Secretory Leukocyte Protease Inhibitor (SLPI), an inhibitor of NF kappa light chain enhancer of activated B cells (NF‐κB) that mediates epithelial hyporesponsiveness to microbial stimuli. Uptake of extracellular SLPI by monocytes has been proposed to inhibit monocyte activation. We questioned whether monocytes can produce SLPI and whether endogenous SLPI can inhibit monocyte activation. We demonstrate that human THP‐1 monocytic cells produce SLPI and that CD68(+) SLPI‐producing cells can be detected in human intestinal lamina propria. Knockdown of SLPI in human THP‐1 cells significantly increased NF‐κB activation and subsequent C‐X‐C motif chemokine ligand 8 (CXCL8) and TNF‐α production in response to microbial stimulation. Reconstitution of SLPI‐deficient cells with either full‐length SLPI or SLPI lacking its signal peptide rescued inhibition of NF‐κB activation and cytokine production, demonstrating that endogenous SLPI inhibits monocytic cell activation. Unexpectedly, exogenous SLPI did not inhibit CXCL8 or TNF‐α production, despite efficient uptake. Our data argue that endogenous SLPI can regulate the threshold of activation in monocytes, thereby preventing activation by commensal bacteria in mucosal tissues.