Penicillium marneffeiCauses Osteopontin-Mediated Production of Interleukin-12 by Peripheral Blood Mononuclear Cells

Abstract

We investigated the role of osteopontin (OPN) in interleukin-12 (IL-12) production from peripheral blood mononuclear cells (PBMCs) stimulated with Penicillium marneffei. Kinetic studies showed that OPN synthesis preceded that of IL-12 at both mRNA and protein levels when PBMCs were cocultured with P. marneffei. Treatment with anti-OPN monoclonal antibodies (MAb) significantly suppressed IL-12 secretion. Furthermore, native OPN induced a profound level of synthesis of IL-12 from noninfected PBMCs. The major cellular source of OPN was monocytes, because depletion of CD14 ؉ cells resulted in the abrogation of such production. We also examined the regulatory role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in OPN secretion from P. marneffei-stimulated PBMCs. Neutralizing anti-GM-CSF MAb significantly reduced OPN secretion, and treatment with this cytokine induced OPN production from both infected and noninfected PBMCs. Finally, antagonists against the mannose receptor but not the ␤-glucan receptor almost completely abrogated the production of OPN. Our results demonstrated that OPN secreted from monocytes is involved in the production of IL-12 from PBMCs after stimulation with P. marneffei and that OPN production is regulated by GM-CSF. Our results also indicated the possible involvement of the mannose receptor as a signaltransducing receptor for triggering the secretion of OPN by P. marneffei-stimulated PBMCs.Penicillium marneffei, an opportunistic fungal pathogen, causes a life-threatening deep-seated systemic infection in patients with AIDS in Southeast Asian countries. The incidence of P. marneffei infection has been increasing among AIDS patients in Thailand since a decade ago (8,12,40). As predicted by the high incidence in these patients, cellular immunity is a central mechanism that mediates host resistance against infection with P. marneffei (18), and CD4 ϩ T cells play an important role in eradicating the microorganisms from infected sites (19). Interleukin-12 (IL-12) protects mice against this infection (17). Furthermore, gamma interferon, generated during the progression of cellular immunity, renders murine macrophages highly active in killing P. marneffei yeast cells, a form usually detected in biological samples from infected patients, by promoting the release of nitric oxide (20).Osteopontin (OPN), a phosphoprotein originally isolated from bone, contains an RGD sequence similar to that of other extracellular matrix and serum proteins, including fibronectin, vitronectin, collagen, thrombospondin, and fibrinogen (7,30,42). OPN promotes integrin-and CD44-mediated cell adhesion and chemotaxis of osteoclasts, smooth muscle cells, macrophages, and T cells (30). OPN production is elevated in various pathophysiological conditions, such as atherosclerosis, nephritis, malignancy, pulmonary fibrosis, wound healing, and bone remodeling (6,9,13,21,28,35,41). OPN is also abundantly produced by T cells and macrophages during the formation of granulomatous lesions in sarcoidosis and tuberculosis (4,25...

Regulatory role of DC‐derived osteopontin in systemic allergen sensitization

“…OPN has been suggested to promote a Th1 response via direct induction of monocyte-or DC-derived IL-12 [30][31][32]. Contrary to these findings, other recent studies have provided evidence that OPN alone is incapable of inducing IL-12p70.…”

Osteopontin: Role in immune regulation and stress responses

“…OPN has been shown to regulate macrophage functions including migration , activation (Rollo and Denhardt, 1996), phagocytosis (McKee and Nanci, 1996), pro-inflammatory cytokine production (Koguchi et al, 2002) and nitric oxide synthesis (Scott et al, 1998) in response to various inflammatory challenges. In the absence of OPN expression, macrophage migration and cytokine production are impaired Sodek et al, 2006).…”

“…OPN's presence in T cell-DC interaction may decisively influence T-cell polarization. This concept is emphasized by the deficiency of Th1 immunity in OPN-deficient mice, which leads to a compromised host defense against bacterial and viral infections (Rollo et al, 2005, Koguchi et al, 2002 and ameliorated autoimmunity (Chabas et al, 2001). with the α v β 3 integrin to induce pro-inflammatory IL-12 and 2) ligation of CD44v to suppress anti-inflammatory cytokine IL-10 production (Ashkar et al, 2000).…”

Osteopontin Is Not Required for the Development of Th1 Responses and Viral Immunity

“…Because OPN has been reported to promote the production of IL-12 from macrophages and monocytes (1,19), and might induce the polarization of naive CD4 T cells to Th1 IFN-␥ producing cells, we wanted to address the role of OPN in the in vitro differentiation of naive CD4 T cells. To 6 PFU of VV-G2 and sacrificed on day 6 for analysis.…”