Glutathione-Redox Balance Regulates c-rel–Driven IL-12 Production in Macrophages: Possible Implications in Antituberculosis Immunotherapy

Alam, Kaiser; Ghousunnissa, Sheikh; Nair, Shiny; Valluri, Vijaya Lakshmi; Mukhopadhyay, Sangita

doi:10.4049/jimmunol.0900439

Cited by 47 publications

(46 citation statements)

References 59 publications

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“…Besides, it is known that interleukin IL-12 (p70) promotes the differentiation of the Th1 cells and the production of IL-2 and IFN-γ thereby supporting cellular immunity, while IL-12 (p40) acts as an antagonist of IL-12 p70 (Suzuki et al 2003;Alam et al 2010). Previous studies have reported that oxidative stress, in particular GSH status, suppresses the IL-12 (p40/p70) production resulting in a Th2 polarized immune response (Murata et al 2002a(Murata et al , 2002bKamide et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…We characterized the secretion of some SASP components in response to oxidative stress (SIPS) and proteasome inhibition induced premature senescence (PIIPS) in primary lung mice fibroblasts and compared them with SASP from replicative senescence (RS). Since the glutathione-redox balance is known to play a significant role in regulating cellular immune responses (Alam et al 2010;Reynaert 2011), GSH/GSSG ratio was determined. Our results showed that SASP profile in RS and SIPS were very similar, but both were very different from PIIPS profile.…”

Section: Introductionmentioning

confidence: 99%

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Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Maciel-Barón

Morales-Rosales

Aquino-Cruz

et al. 2016

AGE

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Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as an important feature during tumor suppression mechanisms and a contributor to aging. Senescent cells have an altered secretion pattern called Senescence-Associated Secretory Phenotype (SASP) that comprises a complex mix of factors including cytokines, growth factors, chemokines, and matrix metalloproteinases. SASP has been related with local inflammation that leads to cellular transformation and neurodegenerative diseases. Various pathways for senescence induction have been proposed; the most studied is replicative senescence due to telomere attrition called replicative senescence (RS). However, senescence can be prematurely achieved when cells are exposed to diverse stimuli such as oxidative stress (stressinduced premature senescence, SIPS) or proteasome inhibition (proteasome inhibition-induced premature senescence, PIIPS). SASP has been characterized in RS and SIPS but not in PIIPS. Hence, our aim was to determine SASP components in primary lung fibroblasts obtained from CD-1 mice induced to senescence by PIIPS and compare them to RS and SIPS. Our results showed important variations in the 62 cytokines analyzed, while SIPS and RS showed an increase in the secretion of most cytokines, and in PIIPS only 13 were incremented. Variations in glutathione-redox balance were also observed in SIPS and RS, and not in PIIPS. All senescence types SASP displayed a pro-inflammatory profile and increased proliferation in L929 mice fibroblasts exposed to SASP. However, the behavior observed was not exactly the same, suggesting that the senescence induction pathway might encompass dissimilar responses in adjacent cells and promote different outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Maciel-Barón

Morales-Rosales

Aquino-Cruz

et al. 2016

AGE

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“…Whole-cell extracts were prepared by using lysis buffer as described earlier (42). The coimmunoprecipitated proteins were detected by Western blotting using appropriate combinations of primary and secondary Abs.…”

Section: Immunoprecipitation Assaymentioning

confidence: 99%

“…Human PBMCs obtained from Lonza (Walkersville, MD) were diluted in RPMI 1640 medium (Invitrogen) containing 10% FBS and seeded in 100-mm petri dish at a density of 20 3 10 6 cells. The MDMs were purified as described elsewhere (42).…”

Section: Cell Culturementioning

confidence: 99%

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Nair

Pandey

Mukhopadhyay

2011

The Journal of Immunology

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Mycobacterium tuberculosis bacteria are known to suppress proinflammatory cytokines like IL-12 and TNF-α for a biased Th2 response that favors a successful infection and its subsequent intracellular survival. However, the signaling pathways targeted by the bacilli to inhibit production of these cytokines are not fully understood. In this study, we demonstrate that the PPE18 protein of M. tuberculosis inhibits LPS-induced IL-12 and TNF-α production by blocking nuclear translocation of p50, p65 NF-κB, and c-rel transcription factors. We found that PPE18 upregulates the expression as well as tyrosine phosphorylation of suppressor of cytokine signaling 3 (SOCS3), and the phosphorylated SOCS3 physically interacts with IκBα–NF-κB/rel complex, inhibiting phosphorylation of IκBα at the serine 32/36 residues by IκB kinase-β, and thereby prevents nuclear translocation of the NF-κB/rel subunits in LPS-activated macrophages. Specific knockdown of SOCS3 by small interfering RNA enhanced IκBα phosphorylation, leading to increased nuclear levels of NF-κB/rel transcription factors vis-a-vis IL-12 p40 and TNF-α production in macrophages cotreated with PPE18 and LPS. The PPE18 protein did not affect the IκB kinase-β activity. Our study describes a novel mechanism by which phosphorylated SOCS3 inhibits NF-κB activation by masking the phosphorylation site of IκBα. Also, this study highlights the possible mechanisms by which the M. tuberculosis suppresses production of proinflammatory cytokines using PPE18.

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“…123. ratio is greater than 1 (>1), thus the host's immunity defense system was dominated by 124. pro-inflammation condition 26 .…”

mentioning

confidence: 99%

Metformin associated inflammation levels regulation in type 2 diabetes mellitus-tuberculosis coinfection patients – A case report

Novita

Soediono

Nugraha

2018

Indian Journal of Tuberculosis

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Glutathione-Redox Balance Regulates c-rel–Driven IL-12 Production in Macrophages: Possible Implications in Antituberculosis Immunotherapy

Abstract: Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/02/15/jimmunol.090043

Cited by 47 publications

References 59 publications

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Metformin associated inflammation levels regulation in type 2 diabetes mellitus-tuberculosis coinfection patients – A case report

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