Interleukin-32 induces the differentiation of monocytes into macrophage-like cells

Abstract

After emigration from the bone marrow to the peripheral blood, monocytes enter tissues and differentiate into macrophages, the prototype scavenger of the immune system. By ingesting and killing microorganisms and removing cellular debris, macrophages also process antigens as a first step in mounting a specific immune response. IL-32 is a cytokine inducing proinflammatory cytokines and chemokines via p38-MAPK and NF-B. In the present study, we demonstrate that IL-32 induces differentiation of human blood monocytes as well as THP-1 leukemic cells into macrophage-like cells with functional phagocytic activity for live bacteria. Muramyl dipepide (MDP), the ligand for the intracellular nuclear oligomerization domain (NOD) 2 receptor, has no effect on differentiation alone but augments the monocyte-to-macrophage differentiation by IL-32. Unexpectedly, IL-32 reversed GM-CSF/IL-4-induced dendritic cell differentiation to macrophage-like cells. Whereas the induction of TNF␣, IL-1␤, and IL-6 by IL-32 is mediated by p38-MAPK, IL-32-induced monocyte-to-macrophage differentiation is mediated through nonapoptotic, caspase-3-dependent mechanisms. Thus, IL-32 not only contributes to host responses through the induction of proinflammatory cytokines but also directly affects specific immunity by differentiating monocytes into macrophage-like cells.immune cell differentiation ͉ inflammation ͉ muramyl dipeptide ͉ cytokine ͉ antigen presentation I n addition to their role for the activation of the antimicrobial function of leukocytes, cytokines have an important role for the proliferation and differentiation of myeloid cell populations. IL-32 is a proinflammatory cytokine that is induced by IL-18 and IFN-␥ in human epithelial cells (1). The gene expression of IL-32 is increased in human T lymphocytes and natural killer cells when stimulated by mitogens or IL-2 (2, 3). In turn, IL-32 also induces the synthesis of proinflammatory cytokines such as IL-1␤, IL-6, and TNF␣. Elevated levels of mRNA have been reported in synovial tissue explants from patients with rheumatoid arthritis, but not osteoarthritis (4). The intensity and frequency of tissue-staining levels of IL-32 protein in synovial cells of patients with rheumatoid arthritis correlate with disease activity, as well as tissue levels of TNF␣, IL-1␤, and IL-18 (5). Affected tissues from patients with Crohn's disease and ulcerative colitis show prominent staining for IL-32 (6, 7). IL-32 is produced by peripheral blood mononuclear cells (PBMCs) stimulated with Mycobacterium tuberculosis (8), and IL-32 acts synergistically with muramyl peptide (MDP) to induce IL-6 via caspase-1-dependent IL-1␤ (6).In vitro, cytokines such as macrophage colony-stimulating factor (M-CSF) induce differentiation of monocytes into macrophages (9), whereas a combination of GM-CSF and IL-4 induces differentiation into dendritic cells (DCs) (10-13). Cytokines such as IL-6 and IFN-␥ can modulate GM-CSF/IL-4-induced monocyte differentiation by switching from DCs to macrophages (10,14). Although IL-6 induces th...

Intracellular Interaction of Interleukin (IL)-32α with Protein Kinase Cϵ (PKCϵ) and STAT3 Protein Augments IL-6 Production in THP-1 Promonocytic Cells

“…IL-32 has even been reported to be a membrane-associated protein that is released via a non-classical secretory pathway (45). IL-32 seems to be multifunctional because it has been shown to induce proinflammatory cytokines (8,39,46), apoptosis (4,47), and cell differentiation (48,49).…”

Interleukin 32 promotes hematopoietic progenitor expansion and attenuates bone marrow cytotoxicity

“…As IL-32 can do both, i.e. induce the development of macrophages from monocytes as well as prevent a GM-CSF/IL-4-dependent differentiation of dendritic cells [30], it could very well function as a hematopoietic growth factor. This dual role was also seen in our results on HPC expansion: when used alone, IL-32 led to twice the number of HPCs, whereas in combination with SCF, IL-32 significantly reduced cell expansion induced by SCF.…”

“…IL-32, another proinflammatory cytokine, is produced by natural killer cells upon stimulation with IL-2. IL-32 can induce the differentiation of monocytes into macrophages, but reverses GM-CSF-induced macrophage differentiation [30]. Representative results of one out of eight independent experiments.…”

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

“…Importantly, another cytokine, IL-32, was recently reported to promote the differentiation of monocytes into macrophage-like cells (22). IL-32 was originally identified as a protein that is highly expressed in activated T and NK cells (23).…”