Myeloid-related Protein (MRP) 8 and MRP14, Calcium-binding Proteins of the S100 Family, Are Secreted by Activated Monocytes via a Novel, Tubulin-dependent Pathway

Abstract

Myeloid-related protein (MRP) 8 and MRP14, two members of the S100 family expressed in myelomonocytic cells, have been ascribed some extracellular functions, e.g. antimicrobial, cytostatic, and chemotactic activities. Since S100 proteins lack structural requirements for secretion via the classical endoplasmic reticulum/Golgi route, the process of secretion is unclear. We now demonstrate the specific, energy-dependent release of MRP8 and MRP14 by human monocytes after activation of protein kinase C. This secretory process is not blocked by inhibitors of vesicular traffic through the endoplasmic reticulum and Golgi, and comparative studies on tumor necrosis factor-alpha and interleukin-1beta indicate that MRP8 and MRP14 follow neither the classical nor the interleukin-1-like alternative route of secretion. Inhibition by microtubule-depolymerizing agents revealed that MRP8/MRP14 secretion requires an intact tubulin network. Accordingly, upon initiation of MRP8/MRP14 secretion, immunofluorescence microscopy showed a co-localization of both proteins with tubulin filaments. Release of MRP8 and MRP14 is associated with down-regulation of their de novo synthesis, suggesting that extracellular signaling via MRP8/MRP14 is restricted to distinct differentiation stages of monocytes. Our data provide evidence that the S100 proteins MRP8 and MRP14 are secreted after activation of protein kinase C via a novel pathway requiring an intact microtubule network.

IFN-γ and TNF Regulate Macrophage Expression of the Chemotactic S100 Protein S100A8

“…S100A9 mRNA or protein was not induced by any mediator tested (Figs. 1 and 3), supporting the notion that coexpression with S100A9 is not essential for S100A8 function or secretion (35). S100A8 protein levels secreted by elicited Mac after stimulation with predetermined optimal amounts of IFN and TNF were higher than those produced by LPS (Fig.…”

“…S100 proteins have no structural sequences required for secretion by the classical endoplasmic reticulum-Golgi pathway, but extracellular functions are well accepted (1). The human S100A8/9 complex may be released via a novel tubulin-dependent mechanism following leukocyte activation (35), suggesting active secretion. We demonstrated mS100A8 in supernatants from LPS-activated Mac cell lines (4) and from IFN and TNF-activated elicited Mac (Fig.…”

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response

“…1 S100/calgranulins, proinflammatory signal transduction ligands of the receptor, are enriched in joints of subjects with rheumatoid arthritis (RA). [2][3][4] Members of this family of molecules, long-associated with classic immune/ inflammatory disorders, 5,6 may be released by activated inflammatory effector cells such as monocytes, 7 thereby freeing them to engage cell surface RAGE and amplify host inflammatory responses. Indeed, accumulation of S100/calgranulins in synovial fluid and plasma of subjects with RA has been correlated with indices of disease severity, such as bony erosions.…”

Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer

“…11). The proteins were suggested to form S100A8/S100A9 heterocomplexes (12,13), which were shown to be secreted by activated monocytes (14). Expression of S100A8 and S100A9 in epithelial tissues was first described in context with squamous epithelia, e.g., various inflammatory skin diseases (15), and with murine and human wound repair (16).…”