Within the secretory pathway, the family of proprotein convertases cleave inactive precursors at paired basic residues to generate a myriad of biologically active peptides. Within the PC family, PC1/3 and PC2 are well known for their preferential expression within neuroendocrine cells. However, various data now indicate their potential expression in immune cells. The aim of our study was two fold: (1) survey PC expression in immune tissues, with emphasis on PC1/3 and PC2 and (2) examine PC expression under conditions that mimic an infectious state using lipopolysaccharide, known to activate immune cells via toll-like receptors. Spatial and temporal analyses of tissues from control and lipopolysaccharide treated rats were carried out using in situ hybridization histochemistry, Northern blot, mass spectrometry and antibacterial assays. Our tissue survey showed the basal expression of all PCs in the lymph nodes, thymus and spleen including PC1/3 and PC2. Focusing on the spleen, basal expression of PC1/3 was seen in the red pulp/marginal zone areas, suggesting expression within macrophages. Lipopolysaccharide treatment produced significant changes in PC1/3 expression and notably an induction in B lymphocytes within germinal centers. Similarly, PC2, which was undetectable in control spleens, was induced in germinal centers following lipopolysaccharide treatment. The PC1/3 and PC2 substrate proenkephalin was also induced following lipopolysaccharide treatment in the marginal zone, where PC1/3 expression was also found. Mass spectrometry analysis of spleen extracts demonstrated the presence of the antibacterial peptide enkelytin. Our studies confirmed that PC1/3 and PC2 expression was not restricted to neurons and endocrine cells, but was also found under basal conditions in both macrophage and lymphocytes. Additionally, plasticity of PC expression in immune cells was observed under conditions that mimic pathogen-like infections, suggesting a mechanistic link through Toll-like receptors. Collectively, these data clearly implicate PCs in immune responses, both innate and acquired.