Surgical Stress Induces Decreased Expression of Signal-Transducing Zeta Molecules in T Cells

Ichihara, Fumiko; Kono, Koji; Sekikawa, Takayoshi; Matsumoto, Yoshirô

doi:10.1159/000008632

Cited by 25 publications

(20 citation statements)

References 18 publications

(36 reference statements)

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“…Consistent with this, rodents and patients with trauma or undergoing liver transplantation have a rapid decrease in circulating L-arginine levels to concentrations below 40 M (11,14), paralleled by poor T cell function (14). In addition, Ichihara et al (39) recently demonstrated the trauma patients may lose CD3 , although they did not associate this change with Larginine reduction. Furthermore, transgenic mice that overexpress ASE I in their enterocytes have a selective depletion of L-arginine in serum, concomitant with a poor thymic development (40).…”

Section: Discussionmentioning

confidence: 92%

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Rodríguez

Zea

DeSalvo

et al. 2003

The Journal of Immunology

417

355

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l-Arginine plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by inducible nitric oxide synthase to produce nitric oxide, important in the cytotoxic mechanisms, and by arginase I (ASE I) and arginase II (ASE II) to synthesize l-ornithine and urea, the first being the precursor for the production of polyamines needed for cell proliferation. l-Arginine availability can modulate T cell function. Human T cells stimulated and cultured in the absence of l-arginine lose the expression of the TCR ζ-chain (CD3ζ) and have an impaired proliferation and a decreased cytokine production. The aim of this work was to test whether activated macrophages could modulate extracellular levels of l-arginine and alter T cell function, and to determine which metabolic pathway was responsible for this event. The results show that macrophages stimulated with IL-4 + IL-13 up-regulate ASE I and cationic amino acid transporter 2B, causing a rapid reduction of extracellular levels of l-arginine and inducing decreased expression of CD3ζ and diminished proliferation in normal T lymphocytes. Competitive inhibitors of ASE I or the addition of excess l-arginine lead to the re-expression of CD3ζ and recovery of T cell proliferation. In contrast, inducible nitric oxide synthase or ASE II failed to significantly reduce the extracellular levels of l-arginine and modulate CD3ζ expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regulation of CD3ζ in cancer and chronic infectious diseases.

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Section: Discussionmentioning

confidence: 92%

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Rodríguez

Zea

DeSalvo

et al. 2003

The Journal of Immunology

417

355

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show abstract

“…Other studies have suggested that increased endogenous NOS (201), reduced oxidative burst (58), and decreased expression of SOD, catalase (CAT), and GSH (260) could potentially lead to T-cellmediated immune responses in SLE. Earlier studies have demonstrated that oxidative stress leads to the downregulation of TCR f-chain expression in patients who have undergone surgery (117). This type of oxidative stressinduced downregulation is seen in T cells isolated from SLE patients (83,84).…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 88%

Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease

Kesarwani

Murali

Al-Khami

et al. 2013

Antioxidants & Redox Signaling

188

165

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“…Patients with severe trauma have a rapid increase in arginase activity in PBMC and profoundly depleted arginine levels in plasma (between 0 and 50 Amol/L). This is accompanied by T-cell anergy and loss of CD3~expression (22,23). Similarly, RCC patients have a decrease in arginine levels compared with normal controls.…”

Section: Discussionmentioning

confidence: 99%

Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

Ochoa

Zea

Hernandez

et al. 2007

Clinical Cancer Research

426

325

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Tumor-induced tolerance is a well-established phenomenon in cancer patients that can severely impair the therapeutic efficacy of immunotherapy. One mechanism leading to T-cell tolerance is the generation of myeloid-derived suppressor cells (MDSC) by soluble factors produced by the tumor. MDSC express CD11b + as a common marker but may vary in their stage of maturation, depending on the tumor factors being produced. Arginase production by MDSC depletes arginine from the tumor microenvironment and impairs T-cell signal transduction and function. We studied whether an increase in MDSC could explain the molecular alterations and dysfunction found in T cells of patients with renal cell carcinoma (RCC). Arginase activity in the peripheral blood mononuclear cells of 117 RCC patients was increased between 6-to 8-fold compared with normal controls. The increased arginase activity was limited to the CD11b + CD14 À myeloid cells and resulted in significantly decreased serum levels of arginine and increased ornithine in patients. Depletion of MDSC restored IFN-g production and T-cell proliferation. Preliminary data suggest that prostaglandin E 2 produced by the tumor induces arginase I expression in MDSC. Therefore, blocking MDSC activity may enhance the therapeutic efficacy of immunotherapy in RCC. Immunotherapy with cytokines, such as interleukin-2 (IL-2),has become a standard of care for patients with renal cell carcinoma (RCC). However, only 20% to 30% of patients have a partial or complete response (1), which is significantly lower than the therapeutic efficacy suggested by animal models. One possible explanation is that tumor-induced tolerance diminishes the potential therapeutic effect of T cells, the principal effector cells in most forms of immunotherapy. Over the last decade, several mechanisms by which tumors escape the immune response have been described. These can be divided into three major groups: alterations in antigen expression in tumor cells to make them less detectable, the active suppression of dendritic and T-cell function by inhibitory molecules or factors produced by tumors, and the induction of cells that can suppress the immune response, including myeloid-derived suppressor cells (MDSC) and regulatory T cells. We have focused our work on characterizing MDSC and the mechanisms by which they cause T-cell dysfunction in cancer.

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Surgical Stress Induces Decreased Expression of Signal-Transducing Zeta Molecules in T Cells

Cited by 25 publications

References 18 publications

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease

Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

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