Osteopontin inhibits inducible nitric oxide synthase activity in rat vascular tissue

Scott, Jeremy A.; Weir, M. Lynn; Wilson, Sylvia M.; Xuan, Jim W.; Chambers, Ann F.; McCormack, David G.

doi:10.1152/ajpheart.1998.275.6.h2258

Cited by 46 publications

(34 citation statements)

References 37 publications

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“…The impact of Opn on type-1 immunity reflects its expression by macrophages, DCs, and activated T cells. The Opn gene is constitutively expressed in macrophages in the absence of deliberate immunization, where it may regulate cellular activation and nitric oxide synthesis in response to bacterial and viral products (24)(25)(26). In contrast, Opn gene expression in T cells is highly inducible upon signaling from the TCR (e.g., Fig.…”

Section: Discussionmentioning

confidence: 99%

T-bet-dependent expression of osteopontin contributes to T cell polarization

Shinohara

Jansson

Hwang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

142

155

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The osteopontin (Opn) glycoprotein has been implicated in diverse physiological processes, including vascularization, bone formation, and inflammatory responses. Studies of its role in immune responses has suggested that Opn can set the early stage of type-1 immune (cell-mediated) responses through differential regulation of IL-12 and IL-10 cytokine gene expression in macrophages. Although Opn has been suggested to play a role in the development of type-1 immunity, little is known about control of Opn gene expression. Here, we report that Opn gene expression in activated T cells, but not macrophages, is regulated by T-bet, a transcription factor that controls CD4 ؉ T helper (Th1) cell lineage commitment. We also find that T-bet-dependent expression of Opn in T cells is essential for efficient skewing of CD4 ؉ T and CD8 ؉ T cells toward the Th1 and type 1 CD8 ؉ T cells (Tc1) pathway, respectively. Taken together, these findings begin to delineate the genetic basis of Opn expression in T cells and further clarify the role of Opn in Th and Tc1 development.genetic programming ͉ T helper 1 development ͉ type-1 immune response T he osteopontin (Opn) glycoprotein has been independently identified and studied by investigators from numerous scientific fields in view of its role in immune responses, vascularization, and bone formation through interactions with mononuclear, endothelial, and bone cells, respectively. Analysis of its contribution to immune responses has suggested that Opn expression can set the stage for protective type-1 immune responses after viral and bacterial infection through differential regulation of IL-12 and IL-10 cytokine production (1-3).Studies of Opn-deficient (Opn Ϫ/Ϫ ) mice have indicated that Opn contributes to host resistance against diverse microbial pathogens including herpes simplex virus 1, Listeria monocytogenes (4), and rotavirus (5). Opn expression is also essential for effective Th1-dependent granuloma formation and a positive clinical outcome in patients suffering from mycobacterial infection (6), whereas ectopic Opn expression has been implicated in the granulomatous lesions of Crohn's disease (7). Dysregulated Opn expression has also been implicated in several autoimmune disorders, including murine experimental autoimmune encephalomyelitis (EAE) (8, 9), multiple sclerosis (10), rheumatoid arthritis (11), and atherosclerosis (12, 13). Dysregulated Opn expression has been correlated with excessive Th1 polarization of CD4 ϩ T cells in these disorders (7,14) opening the possibility that Opn gene expression may directly contribute to Th1͞type 1 CD8 ϩ T cells (Tc1) genetic programming. However, the genetic basis of Opn expression in Th-cell subsets is not well understood.T-bet, a member of the T box family of transcription factors, is the master coordinator of gene expression in T cells that initiate type-1 immunity and is essential for Th1 cell polarization (15). Thus, T-bet deficiency reduces IFN-␥ production by activated CD4 ϩ T cells and T cell antigen receptor (TCR)-transgenic CD8...

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Section: Discussionmentioning

confidence: 99%

T-bet-dependent expression of osteopontin contributes to T cell polarization

Shinohara

Jansson

Hwang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

142

155

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“…Extensive studies have recently clarified that OPN is widespread and localized in several pathological organs and has important roles in ectopic calcification [6,8], wound healing [4], several types of cancer [15,18], and vascular remodeling, including diabetic condition [7][8][9][10][11][12][13][14], granulomatous inflammation [3], and glomerulonephritis [5,19]. Although the clinical implications of these findings have yet to be fully clarified, it is more likely that OPN can, at least, evolve as a major player in the injury/repair cascades.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, several investigators have recently revealed that OPN can play multiple roles in the progression of atherosclerotic plaque [7][8][9][10][11][12][13][14] including diabetic vascular complications [12][13][14]. Particularly in diabetes, OPN has the potential to promote both the growth and migration of vascular wall cells such as VSMCs [9,10,12,14] and mesangial cells [13], depending on the glucose concentration.…”

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confidence: 99%

Progression of Diabetic Nephropathy Enhances the Plasma Osteopontin Level in Type 2 Diabetic Patients

et al. 2004

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Abstract. Osteopontin (OPN) is thought to play multiple roles in the progression of atherosclerotic plaque including diabetic vascular complications. However, it still remains unclear whether the level of OPN in vivo is indeed clinically associated with the progression of diabetic complications. This study evaluated whether the levels of OPN in plasma and urine are correlated with the progression of diabetic complications, such as retinopathy, neuropathy, and nephropathy in patients with type 2 diabetes. In 229 patients with type 2 diabetes, OPN level in plasma and urine was evaluated by both the severity of diabetic complications, such as retinopathy, neuropathy, and nephropathy, and the clinical characteristics and the substantial laboratory findings. Plasma OPN level increased significantly with aging and the progression of diabetic nephropathy, especially at the stage of renal failure (p<0.05). However, the level was not related to the progression of retinopathy or neuropathy, or to laboratory findings, such as HbA1c or serum lipids. In contrast, urinary OPN level was not associated with diabetic complications in any of the subjects. There was no correlation between the plasma and urinary values of OPN. The results established that the plasma OPN was elevated in proportion to the progression of diabetic nephropathy, indicating that the plasma concentration may be a potential diagnostic predictor of diabetic end-stage renal disease.

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“…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).…”

Section: Macrophagesmentioning

confidence: 99%