Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype

Abstract

IntroductionOsteopontin (OPN) is a secreted phosphoprotein that contains an integrin-binding arginine-glycine-aspartate sequence (RGD) motif. OPN has proinflammatory cytokine and chemokine functions in cell-mediated immunity. [1][2][3][4] A number of studies have demonstrated that OPN critically contributes to the development of T helper 1 (Th1)-mediated immunity and disease. 5,6 Among other reports, OPN-deficient mice develop disseminated infection and have a delayed ability to clear disease when infected with Mycobacterium bovis (BCG). 7 In murine models of autoimmune encephalomyelitis, a model of human multiple sclerosis that critically depends upon the balance of Th-shaping cytokines such as interleukin-10 (IL-10) and IL-12, OPN-deficient mice develop milder disease. 8,9 Corneal infection of OPN-deficient mice with herpes simplex virus 1 (HSV-1) is followed by a reduced delayedtype hypersensitivity to HSV. 6 We have shown that OPN-deficient mice have an impaired allergic contact hypersensitivity (CHS) response against trinitrochlorobenzene, which is accompanied by a reduced ability to attract dendritic cells (DCs) from the periphery into draining lymph nodes. 10 DCs are the most potent antigen-presenting cells (APCs). Their function and polarizing capacities are decisive for the outcome of Th-mediated immunity. [11][12][13] Although, it is known that OPN plays a central role for the initiation of Th1-mediated immune responses, it is unknown whether it is involved in DC instruction to induce Th1-mediated responses. In their immature state, DCs are situated in peripheral nonlymphoid tissues. 14,15 For example, Langerhans cells (LCs) are located in the epidermis. Upon stimulation, LCs/DCs undergo a maturation process resulting in the downregulation of their antigen uptake and processing capacity; upregulation of major histocompatibility complex (MHC) II and costimulatory molecules; and a switch in their expression pattern of chemokines and adhesion molecules. 14,15 As a consequence of this reprogramming, DCs migrate into lymphoid organs. 16,17 In the T-cell zone of lymph nodes, they function as APCs, which prime naive antigen-specific T cells and drive their differentiation toward Th1, Th2, or regulatory T cells. [11][12][13] The initial activation stimulus in concert with tissue environmental factors encountered by migrating DCs instruct DCs to polarize toward a phenotype that initiates Th1, Th2, or regulatory T effector cells. 11,12,18,19 Numerous viral and microbial factors, among them lipopolysaccharide (LPS), Staphylococcus aureus Cowan strain I, bacterial DNA and dsRNA, [20][21][22][23][24] and Pertussis toxin in the context of IL-1␤ and tumor necrosis factor ␣ (TNF-␣), 25 have been described as IL-12-and Th1-prompting factors. In contrast, substances that increase intracellular cyclic adenosine monophosphate (cAMP), such as cholera toxin 26 For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Incomplete knowledge exists regarding tissue factors that are encountered by DCs on their w...

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

“…Based upon the studies in autoimmune animal models and those in rheumatoid arthritis in humans, OPN could be an important cytokine to be targeted as it is highly related to autoimmunity [10,13,30,50,[53][54][55]. The other important role of OPN is related to migration of inflammatory cells into the CNS [56].…”

“…Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages [9][10][11][12]. Further, its role as a pro-inflammatory cytokine has been implicated in rheumatoid arthritis and other autoimmune conditions [13].…”

“…Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages [9][10][11][12]. Further, its role as a pro-inflammatory cytokine has been implicated in rheumatoid arthritis and other autoimmune conditions [13].…”

Osteopontin: Role in immune regulation and stress responses

“…OPN-deficient mice have shown a significantly reduced contact hypersensitivity reaction possibly due to an impaired ability to attract Langerhans cells/DCs to draining lymph nodes. OPN-activated DCs produce IL-12 and TNF-α, and when incubated with naïve T cells, can induce naïve T cells into Th1-polarizing, IFN-γ-producing T cells (Renkl et al, 2005). OPN's presence in T cell-DC interaction may decisively influence T-cell polarization.…”

“…OPN has been identified as a major factor in the regulation of immune responses and inflammation; its expression is up-regulated in activated T cells, macrophages and NK cells Shinohara et al, 2005). It is classified as a Th1 cytokine because it enhances production of the Th1 cytokines IFN-γ and IL-12 and inhibits production of the Th2 cytokine IL-10 by macrophages (Ashkar et al, 2000;Renkl et al, 2005). The roles that OPN plays in mammalian systems physiology are diverse.…”