Conversion of Proepithelin to Epithelins

Abstract

Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI) leads to impaired wound healing due to enhanced activity of TGFbeta and perhaps additional mechanisms. Proepithelin (PEPI), an epithelial growth factor, can be converted to epithelins (EPIs) in vivo by unknown mechanisms with unknown consequences. We found that PEPI and EPIs exert opposing activities. EPIs inhibit the growth of epithelial cells but induce them to secrete the neutrophil attractant IL-8, while PEPI blocks neutrophil activation by tumor necrosis factor, preventing release of oxidants and proteases. SLPI and PEPI form complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrects the wound-healing defect in SLPI null mice. Thus, SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing.

Cartilage Oligomeric Matrix Protein Associates with Granulin-Epithelin Precursor (GEP) and Potentiates GEP-stimulated Chondrocyte Proliferation

“…GEP itself is a secreted growth factor with high molecular weight that is involved in various biological and pathological processes, including mesothelial differentiation (44), sexual differentiation of the brain (45), macrophage development (46), rheumatoid arthritis and osteoarthritis (47), and wound response and tissue repair (38,48). In some cases, GEP may be processed into small 6-kDa peptides, which may be stored in vesicles in the neutrophil.…”

“…Elastase digests GEP exclusively in the interepithelin linkers, resulting in the generation of granulin peptides, suggesting that this protease may be an important component of a GEP convertase. Secretory leukocyte protease inhibitor blocks this proteolysis either by directly binding to elastase or by sequestering epithelin peptides from the enzyme (48). It was found that GEP can modulate transcription activities by interacting with human cyclin T1, a component of positive transcription elongation factor b (58), and Tat-positive transcription elongation factor b (57).…”

“…It has been isolated as a differentially expressed gene from mesothelial differentiation (44), sexual differentiation of the brain (45), macrophage development (46), and synovium of rheumatoid arthritis and osteoarthritis (47). Remarkably, GEP was also shown to be a crucial mediator of wound response and tissue repair (38,48).…”

A Novel Hematopoietic Granulin Induces Proliferation of Goldfish (Carassius auratus L.) Macrophages

“…Granulins were first purified from the extracts of human inflammatory cell exudates, and from rat bone marrow (1). To date, seven granulin peptides (A to G) have been characterized (9,10,26,27), and it has been shown that they are generated following proteolytic cleavage of progranulin (7). The two main differences between goldfish granulin and mammalian progranulin were: (a) the goldfish granulin gene encoded for a much smaller protein (159 amino acids); and (b) unlike mammalian progranulin, which has been shown to be expressed ubiquitously in different tissues, the goldfish granulin expression was limited to hematopoietic tissues (kidney and spleen) and blood mononuclear cells.…”

“…First identified as small (6 kDa) peptides, granulins are produced by the proteolysis of a larger precursor molecule by leukocyte derived elastase activity (1)(2)(3)(4)(5)(6)(7). The larger precursor is known by several names, including granulin/epithelin precursor (8), proepithelin (9), acrogranin (10), PC cell-derived growth factor (PCDGF) (11), and progranulin.…”