J Interferon Cytokine Res. 2015 Nov;35(11):875-87. doi: 10.1089/jir.2014.0210.

Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals.

 

Ly J1,2, Saing T1, Lagman M1,2, Singh MK1,2, Tudela EV1,2, Morris D2, Anderson J2, Daliva J2, Ochoa C3, Patel N3,Pearce D4, Venketaraman V1,2.

  • 1Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California.
  • 2Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California.
  • 3Western Diabetes Institute, Pomona, California.
  • 4Center for Comparative Effectiveness and Outcomes Research, Loma Linda University, Loma Linda, California.

 

Abstract

Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.

PMID: 26133750

 

Supplement:

Tuberculosis (TB) remains an eminent global burden with one third of the world’s population latently infected with M. tb. Individuals with compromised immune system such as those with HIV infection and with Type 2 Diabetes Mellitus (T2DM) are highly vulnerable to M. tb infection. We recently reported that individuals with T2DM and people with HIV infection have diminished levels of GSH due to compromised levels of GSH synthesis and metabolism enzymes (1-5). Transforming growth factor beta (TGF-β), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in HIV-infected subjects and individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH (1-5). Moreover, increased levels of pro-inflammatory cytokines such as IL-6 and IL-17 were observed in HIV positive subjects and individuals with T2DM [Fig 1]. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in this highly susceptible population (1-5) [Fig 1]. Augmenting the levels of GSH in macrophages isolated from HIV-infected individuals and subjects with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as TNF-α, IL-1β, IL-2, IFN-γ, and IL-12, were found to be compromised in HIV positive subjects and individuals with T2DM (1-5). On the other hand, IL-10, an immunosuppressive cytokine was increased in plasma samples isolated from HIV positive subjects and individuals with T2DM (1-5) [Fig 1].

fig1

We also demonstrated in the autopsied human brain tissues that the levels of total and reduced forms of GSH were significantly compromised in HIV infected individuals compared to healthy subjects [Fig 3]. Brain tissue samples derived from HIV-positive individuals had substantially higher levels of free radicals than healthy individuals. Enzymes that are responsible for the de novo synthesis of GSH such as GCLC and GSS were significantly decreased in the brain tissue samples derived from HIV-positive individuals compared to healthy individuals. Overall, these findings suggest that lower levels of GSH in HIV infection and T2DM could lead to increased susceptibility to M. tb infection. Furthermore, GSH deficiency in the brain tissue from HIV infected individuals will further enhance the risk for susceptibility to TB meningitis, the most severe form of extra-pulmonary TB.

fig2

Importantly, results from our recently conducted clinical trial indicate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH-Your Energy Systems) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ and TNF-a (5) [Fig 2].  lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines (IL-10 and TGF-β), along with improved control of M. tb infection relative to those in a placebo-controlled cohort (5). Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection via TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.

fig3

References:

  1. Morris D, Guerra C, Donahue C, Oh H, Khurasany M and Venketaraman V (2012). Unveiling the mechanisms for decreased glutathione in individuals with HIV infection. Clinical and developmental immunology. 12:734125.
  2. Morris D,  Guerra  C,  Khurasany M,  Guilford  F,  Saviola  B,  Huang  Y  and  Venketaraman  V  (2013).  Glutathione supplementation improves macrophage functions in HIV.  Journal of Interferon and cytokine research. 33 (5):270-9.
  3. Morris, D; Ly, J; Chi, P; Daliva, J; Nguyen, T; Soofer, C; Chen, Y; Lagman, M; Venketaraman, V. (2014). Glutathione synthesis is compromised in erythrocytes from individuals with HIV. Frontiers in Pharmacology. 5 (73) 1-6.
  4. Minette, L; Ly, J; Saing, T; Singh, M; Tudela, E;  Morris D,   Chi, P; Ochoa, C; Sathananthan, A; Venketaraman, V (2015). Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. PLoS One. Mar 19; 10(3):e0118436.
  5. Ly, J; Minette, L; Saing, T; Singh, M; Tudela, E;  Morris D,  Anderson J; Daliva J; Ochoa, C; Patel, N; Pearce D and Venketaraman, V (2015). Liposomal Glutathione Supplementation Restores Appropriate Cytokine Response to Intracellular Mycobacterium tuberculosis Infection in HIV Infected Individuals. Journal of Interferon and cytokine research. 2015. July 2.

 

ACKNOWLEDGEMENTS:

We thank the University of California-Irvine – ADRC Brain Tissue Repository for providing us with the brain tissue samples from healthy subjects and individuals with Alzheimer’s disease.  We are grateful to the National NeuroAIDS Tissue Consortium (NNTC), U.C. San Diego for providing us with the brain tissue samples from individuals with HIV infection. We acknowledge the funding support from American Heart Association, Potts Memorial Foundation, Your Energy Systems and Western University of Health Sciences

 

fig4Contact information:

Vishwanath Venketaraman, Ph. D.

Associate Professor

Microbiology/Immunology

Department of Basic Medical Sciences

College of Osteopathic Medicine of the Pacific

Western University of Health Sciences

309 E Second Street, Pomona, CA 91766-1854

Phone: 909-706-3736; Fax: 909-469-5698

Email: vvenketaraman@westernu.edu

http://www.westernu.edu/stp/bios.php?bio=vvenketaraman

 

 

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