An adverse immune-endocrine profile in patients with tuberculosis and type 2 diabetes

Fernández, R; Díaz, Ariana; D’Attilio, Luciano; Bongiovanni, Bettina; Santucci, Natalia; Bértola, Diego; Besedovsky, Hugo O.; Rey, Adriana del; Bay, María Luisa

doi:10.1016/j.tube.2016.09.001

Cited by 10 publications

(14 citation statements)

References 38 publications

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“…In a previous study, treatment with DHEA starting on day 60 after Mtb infection in BALB/c mice reduced the pulmonary bacillary burden and decreased tissue damage by reactivating the Th1 cytokine response (37). In humans, a deficit in DHEA relative to cortisol can be striking in severe TB (12). However, DHEA is suboptimal for human use, partly because it is metabolized into sex steroids.…”

Section: Discussionmentioning

confidence: 99%

“…GCs inhibit the proliferation of effector T cells and induce apoptosis of neutrophils, basophils and eosinophils, resulting in reduced inflammation (11). In homeostatic conditions and under acute stress, the principal source of GCs are the adrenal glands, which are regulated by the negative feedback loop of the hypothalamus-pituitary-adrenal (HPA) axis (12). However, diverse environmental insults and metabolic or endocrine alterations prompt GCs over-production, leading to negative effects on metabolism and the immune response (13).…”

Section: Introductionmentioning

confidence: 99%

“…This hormone displays antagonistic activity to cortisol, counteracting the deleterious effect of cortisol on immune response ( 21) and glucose metabolism. The cortisol-DHEA ratio is modified in T2D/TB co-morbidity and represents a deleterious factor for both diseases (12). However, the anabolic effects of DHEA prevents its pharmacological use in the treatment of these diseases.…”

Section: Introductionmentioning

confidence: 99%

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16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

López-Torres

Marquina‐Castillo

Ramos-Espinosa

et al. 2021

Clinical and Experimental Immunology

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Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1).11-βHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv.Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-βHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular | 233

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

López-Torres

Marquina‐Castillo

Ramos-Espinosa

et al. 2021

Clinical and Experimental Immunology

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“…A typical example of this comes from tuberculosis (TB), a major public health problem today. We demonstrated that pulmonary TB coexists with augmented plasma levels of IL-1β and IL-6, among others, along with unbalanced levels of adrenal steroids (decreased and increased dehydroepiandrosterone [DHEA] and cortisol amounts, respectively), unfavorable for the disease course, in terms of the disturbed anti-infective response, control of tissue damage, and metabolism [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1β on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As

Santucci

Stampone

Silva

et al. 2020

Neuroimmunomodulation

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Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone – DHEA) release by the adrenal gland. While IL-1β modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. Method: We studied the effect of IL-1β on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1β-treated NCI-H295R cells. Results: Transcripts encoding IL-1β receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on them. The miRNA profile was modified by IL-1β treatment to an extent which bears some relationship with the regulatory mechanisms underlying adrenal steroid production. Since orphan nuclear receptors NR4As have emerged as potential key factors for coordinating inflammatory and metabolic responses, cell expression studies were also carried out to show an NR4As transcript augmentation following IL-1β treatment. Discussion/Conclusions: The subtle increase in adrenal steroid production in response to IL-1β stimulation without any modification in the transcription of the steroidogenic enzymes analyzed suggests an additional inflammatory/anti-inflammatory loop, wherein NR4As receptors may participate. Besides its physiological role, this process might be implied in pathological states accompanied by an unbalanced immune-endocrine relationship.

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“…A new aspect in understanding the higher susceptibility of T2D to develop TB is the study of the abnormal metabolic factors and neuro-immune-endocrine regulation in this co-morbidity. In homeostatic conditions and under acute or chronic stress, the principal source of glucocorticoids (GCs) are the adrenal glands regulated by the activation of the Hypothalamus-Pituitary-Adrenal (HPA) axis (8). Besides this source of circulating GCs, there is a local organ conversion of inactive to active GCs (9), which is mediated by the enzyme 11-β-hydroxysteroid dehydrogenase type 1 ) that has an oxo-reductase activity using NADP(H) as a cofactor.…”

Section: Introductionmentioning

confidence: 99%

16a-Bromoepiandrosterone as a new candidate for diabetes-tuberculosis comorbidity treatment

Torres¹,

Marquina²,

Ramos-Espinosa³

et al. 2020

Preprint

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Being the leading cause of mortality by a single infectious agent, tuberculosis (TB) continues as one of the most relevant issues of public health. Another pandemic disease is type 2 diabetes mellitus (T2D) is usually associated with immunodeficiency. Thus, an increased prevalence of TB-T2D comorbidity represents one of the most significant challenges for health providers. During the chronic phase of both diseases, several immunoendocrine abnormalities are occurring, but extra-adrenal production of active glucocorticoids (GCs) is a possible deleterious factor in both entities. Active GCs have been related to insulin resistance and suppression of Th1 responses, contributing to T2D and TB pathogenesis. 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) catalyzes the conversion of inactive GGs in their active form (cortisol or corticosterone in rodents) in the lungs and liver and could be responsible for this immunoendocrine disfunction. Dehydroepiandrosterone (DHEA) is an anabolic adrenal hormone with antagonist effects against GCs on immune cells and glucose metabolism. A synthetic analog of DHEA, the 16abromoepindrosterone (BEA), lacks an anabolic effect while keeping his immune and metabolic effect. The therapeutic efficiency of BEA was studied in a murine model of T2D-TB comorbidity. TB-T2D mice underwent more severe lung disease than in TB-infected but non-diabetic animals. BEA decreased the active form of GCs and 11-βHSD1 expression, while increasing 11-βHSD2 expression, which reduced hyperglycemia and liver steatosis, lung bacillary loads, and pneumonia. Thus, it seems that BEA is an efficient therapy to control metabolic and immune abnormalities caused by high active GCs production.

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An adverse immune-endocrine profile in patients with tuberculosis and type 2 diabetes

Cited by 10 publications

References 38 publications

16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1β on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As

16a-Bromoepiandrosterone as a new candidate for diabetes-tuberculosis comorbidity treatment

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