Associations of Circulating Soluble Tumor Necrosis Factor-α Receptors 1 and 2 with Interleukin-6 Levels in an Aging Cohort of Injection Drug Users with or at High Risk for HIV Infection

Abstract

Chronic inflammation marked by elevated interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptor (sTNFR)-1, and sTNFR-2 levels may play a detrimental role in aging and HIV infection. This study aimed to evaluate the relationships of circulating IL-6 with sTNFR-1 and sTNFR-2 levels in an aging cohort of injection drug users (IDUs) with or at high risk for HIV infection. The AIDS Linked to the Intravenous Experience (ALIVE) study is a community-recruited, prospective observational study of former and current IDUs in Baltimore, Maryland. Serum IL-6, sTNFR-1, and sTNFR-2 levels were measured using standard ELISA. Multivariate linear regression analysis was employed, adjusting for age, sex, HIV status, injection drug use, comorbidities, as well as HIV viral load, CD4 T cell counts, and antiretroviral therapy where appropriate. The analysis included 1,178 participants (316 HIV positive and 862 HIV negative). In the adjusted model, sTNFR-1 and sTNFR-2 were individually associated with IL-6 (regression coefficient: 0.877 and 0.556, respectively, for all participants; 0.607 and 0.407 for HIV positives; and 0.999 and 0.628 for HIV negatives, all p < 0.0001). In the model combining sTNFR-1 and sTNFR-2, the associations for sTNFR-1 remained significant (0.693 for all participants, p < 0.0001; 0.417 for HIV positives, p < 0.05; and 0.840 for HIV negatives), while those for sTNFR-2 were no longer significant. sTNFR-1 and sTNFR-2 were positively associated with IL-6 in ALIVE participants. These findings provide initial insight into the in vivo relationship between TNF-α activation and IL-6 and a basis for further investigations into potential mechanisms underlying chronic inflammation in aging and HIV infection.

Chronic Low-grade Inflammatory Phenotype (CLIP) and Senescent Immune Dysregulation

“…By successfully targeting this upstream mediator, monoclonal antibodies against TNF-a have now become an indispensable armamentarium to treat rheumatoid arthritis. 9,56 In another analysis, when serum neopterin and CRP levels were added to the analysis described above, 55 we observed that neopterin was differentially associated with sTNFR-1 and sTNFR-2 rather than IL-6 or CRP. 57 These findings indicate that neopterin, being a mediator of immune activation, is associated with more proximal inflammatory mediators (sTNFR-1 and sTNFR-2) instead of distal mediators (IL-6 and CRP), suggesting a potential interventional target upstream of CRP and IL-6 that deserves further investigation.…”

“…We conducted an analysis to evaluate the relationships between serum levels of IL-6 and sTNFR-1 and sTNFR-2 in the AIDS Linked to the Intra Venous Experience study, a large prospective cohort study of injection drug users, and found significant associations of IL-6 with sTNFR-1 and sTNFR-2. 55 This finding has led to the notion that TNF-a may serve as a key mediator that triggers or regulates the inflammatory pathway in CLIP with therapeutic implications. This is because TNF-a is a central player in the inflammatory cascade leading to systemic inflammation.…”

Aging, sex, inflammation, frailty, and CMV and HIV infections

“…Of note, CLIP encompasses many molecular mediators, likely forming a complex and interactive network. In fact, analyses of five CLIP mediators measured in the ALIVE study at baseline demonstrate that while soluble TNF-α receptors I and II levels were highly associated with IL-6 levels [46], levels of neopterin, an upstream immune activation mediator, was associated only with levels of soluble TNF-α receptors I and II levels, not with those of more distal and downstream inflammatory mediators IL-6 and CRP [47], suggesting potential a network of upstream vs downstream or proximal vs distal CLIP mediators in HIV infection with therapeutic implications.…”

Differential Relationships among Circulating Inflammatory and Immune Activation Biomediators and Impact of Aging and Human Immunodeficiency Virus Infection in a Cohort of Injection Drug Users

“…In the ALIVE study, we have also shown significant associations of serum levels of IL-6 and sTNFR-1 as well as an aggregate inflammatory index including IL-6 and sTNFR-1 levels with frailty and mortality ( 38 ). In addition, we have demonstrated significant in vivo associations between IL-6 and sTNFR-1 and sTNFR-2 levels ( 39 ). However, these are primarily biomediators of chronic inflammation.…”