Anti-inflammatory cytokines IL-27, IL-10, IL-1Ra and TGF-β in subjects with increasing grades of glucose intolerence (DM-LTB-2)

Highlights

• High serum levels of anti-inflammatory cytokines was seen in the LTB^-PDM, compared to LTB^-NGT group.

• Increased IL-27 and IL-10 levels were seen in the LTB^-NDM, compared to LTB^-NGT group.

• TB antigen induced secretion of IL-1Ra was absent in LTB⁺KDM group.

• Both glucose intolerance and LTBI modulated systemic levels and in vitro secretion of anti-inflammatory cytokine.

Abstract

Anti-inflammatory cytokines act as double edged swords- they can dampen inflammation but can also suppress immunity. The role played by these cytokines in latent TB infected (LTBI) subjects, with various grades of glucose intolerance was studied. Both serum levels and recall-secretion of IL-27, IL-10, IL-1Ra and TGF-β in Normal Glucose Tolerance (NGT), Pre-Diabetes (PDM), Newly diagnosed Diabetes (NDM) and Known Diabetes (KDM) subjects, both with and without LTBI (n = 382), were quantified by ELISA. All the subjects were screened for LTBI by QuantiFERON-TB Gold test. Serum levels of IL-27, IL-10 and IL-1Ra were significantly elevated in the LTB^-PDM, compared to LTB^-NGT group. Increased IL-27 and IL-10 levels and decreased levels of TGF-β were seen in the LTB⁻NDM, compared to LTB⁻NGT group. Decreased serum levels of IL-27 and increased levels of IL-1Ra and TGF-β were seen in the LTB⁻KDM, compared to LTB⁻NGT group. TB antigens induced the secretion of IL-1Ra in LTB⁺ subjects in the NGT, PDM and NDM groups, but not in the KDM group. Co-morbidity with LTBI brought about (diabetic) stage-specific modulation, in these cytokine levels. Major defects in the circulating levels and recall secretion of anti-inflammatory cytokines, as seen in LTB⁺KDM subjects, could fuel DM-TB synergy.

Introduction

TB patients with diabetes have higher sputum bacillary load, delayed bacterial clearance, and higher rates of multidrug- resistance [1]. Recent epidemiological surveys have clearly shown the possibility of diabetes-tuberculosis (DM-TB) nexus in near future [1]. Thus, these issues require urgent attention [1], [2]. Previously, we and others have shown increased prevalence of pre-diabetes and diabetes among TB patients [3], [4]. The exact reason behind this DM-TB synergy is not known. It could, either be due to higher reactivation of latent tuberculosis infection (LTBI) or due to higher rate of infection [5]. Chronic hyperglycemia can impair anti-TB immunity which can augment latent TB activation or increase the TB infection [6]. Previously, we have reported reduced serum levels of chemokines in diabetes patients with tuberculosis, as one of the possible mechanism behind this nexus [7].

Anti-inflammatory cytokines can dampen inflammation in diabetes, but can also impair immunity and can fuel DM-TB nexus [8]. While IL-10, TGF-β and IL-1Ra are the well characterized anti-inflammatory cytokines, IL-27 is a recently discovered novel cytokine with strong anti-inflammatory properties [9], [10]: In diabetes, they dampen inflammation and thereby insulin resistance [11]; in TB, they suppress the immunity and promote reactivation [12]. Recently, we found decreased prevalence of LTB in PDM and NDM groups compared to NGT and KDM groups (manuscript in preparation). We also found significantly elevated levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in these groups, conferring protection against LTBI (manuscript in preparation). This prompted us to look at the levels of anti-inflammatory cytokines (IL-27, IL-10, IL-1Ra and TGF-β) in these groups. Thus, in the present study both systemic levels and recall secretion of anti-inflammatory cytokines were studied in LTBI subjects with various grades of glucose intolerance.