Elastase and Tryptase Govern TNF alpha-Mediated Production of Active Chemerin by Adipocytes
Parlee, Sebastian D.
McNeil, Jenna O.
Sinal, Christopher J.
Goralski, Kerry B.
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Chemerin is a leukocyte chemoattractant and adipokine with important immune and metabolic roles. Chemerin, secreted in an inactive form prochemerin, undergoes C-terminal proteolytic cleavage to generate active chemerin, a ligand for the chemokine-like receptor-1 (CMKLR1). We previously identified that adipocytes secrete and activate chemerin. Following treatment with the obesity-associated inflammatory mediator TNF alpha, unknown adipocyte mechanisms are altered resulting in an increased ratio of active to total chemerin production. Based on these findings we hypothesized adipocytes produce proteases capable of modifying chemerin and its ability to activate CMKRL1. 3T3-L1 adipocytes expressed mRNA of immunocyte and fibrinolytic proteases known to activate chemerin in vitro. Following treatment with a general protease inhibitor cocktail (PIC), the TNF alpha-stimulated increase in apparent active chemerin concentration in adipocyte media was amplified 10-fold, as measured by CMKLR1 activation. When the components of the PIC were investigated individually, aprotinin, a serine protease inhibitor, blocked 90% of the TNF alpha-associated increase in active chemerin. The serine proteases, elastase and tryptase were elevated in adipocyte media following treatment with TNF alpha and their targeted neutralization recapitulated the aprotinin-mediated effects. In contrast, bestatin, an aminopeptidase inhibitor, further elevated the TNF alpha-associated increase in active chemerin. Our results support that adipocytes regulate chemerin by serine protease-mediated activation pathways and aminopeptidase deactivation pathways. Following TNF alpha treatment, increased elastase and tryptase modify the balance between activation and deactivation, elevating active chemerin concentration in adipocyte media and subsequent CMKLR1 activation.
Parlee, Sebastian D., Jenna O. McNeil, Shanmugam Muruganandan, Christopher J. Sinal, et al. 2012. "Elastase and Tryptase Govern TNF alpha-Mediated Production of Active Chemerin by Adipocytes." Plos One 7(12): 51072-e51072.