Granulysin, a Cytolytic Molecule, Is Also a Chemoattractant and Proinflammatory Activator

Abstract

Granulysin, a cationic protein produced by activated human CTL and NK cells, is cytolytic against microbial and tumor targets. In this study we show that granulysin also functions as a chemoattractant and activates monocytes to produce cytokines/chemokines. Although granulysin-mediated cytotoxicity occurs at micromolar concentrations, chemoattraction occurs in the nanomolar range, and immune activation occurs over a wide range of concentrations (nanomolar to micromolar). Granulysin causes a 2- to 7-fold increase in chemotaxis of monocytes, CD4+, and CD8+ memory (CD45RO) but not naive (CD45RA) T cells, NK cells, and mature, but not immature, monocyte-derived dendritic cells. Pertussis toxin treatment abrogates chemoattraction by granulysin, indicating involvement of G-protein-coupled receptor(s). At low concentrations (10 nM), granulysin promotes a 3- to 10-fold increase in MCP-1 and RANTES produced by monocytes and U937 cells, while a 2-fold increase in TNF-α production by LPS-stimulated monocytes requires higher concentrations of granulysin (micromolar). Taken together, these data indicate that the local concentration of granulysin is critical for the biologic activity, with high concentrations resulting in cytotoxicity while lower concentrations, presumably further from the site of granulysin release, actively recruit immune cells to sites of inflammation.

High Cytotoxic and Specific Migratory Potencies of Senescent CD8+CD57+ Cells in HIV-Infected and Uninfected Individuals

“…This protein is present in the cytotoxic granules of CTL and NK cells and is a critical effector of the antimicrobial activity of CTLs against intracellular pathogens (37,38). Granulysin is also a chemoattractant and a proinflammatory activator that actively recruits immune cells to inflammation sites (39), and its presence shows that the antiviral role of CD8 ϩ CD57 ϩ cells involves mechanisms other than direct lysis of HIV-infected cells.…”

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

“…Another mechanism by which this molecule induces cell death is through caspase-3 activation (92). The function of granulysin is not only limited to cytolysis but is also a leukocyte chemoattractant or activator at nano-molar concentrations in an inflammatory environment (94). In just micromolar concentrations, granulysin causes cellular lysis, thus this molecule plays an important role in the field of rejecting allografts (95).…”

Severe Cutaneous Adverse Reactions

“…This contrasted with the minimal cytotoxicity induced by perforin, granzyme B, and FasL [48]. Granulysin is also a proinflammatory molecule that causes an increase in the expression of chemokines (RANTES/CCL5, MCP-1, MCP-3, MIP-1α/CCL3) and cytokines (IL-1, IL-6, IFN-α) resulting in the recruitment of T cells, monocytes and other inflammatory cells [50].…”