Tumor Necrosis Factor-α in Heart Failure: an Updated Review

Abstract

Purpose of the review: Proinflammatory cytokines are consistently elevated in congestive heart failure. In the current review, we provide an overview on the current understanding of how tumor necrosis factor-α (TNFα), a key proinflammatory cytokine, potentiates heart failure by overwhelming the anti-inflammatory responses disrupting the homeostasis.

Recent findings: Studies have shown co-relationship between severity of heart failure and levels of the proinflammatory cytokine TNFα and one of its secondary mediators interleukin-6 (IL-6), suggesting their potential as biomarkers. Recent efforts have focused on understanding the mechanisms of how proinflammatory cytokines contribute towards cardiac dysfunction and failure. In addition, how unchecked proinflammatory cytokines and their cross-talk with sympathetic system overrides the anti-inflammatory response underlying failure. The review offers insights on how TNFα and IL-6 contribute to cardiac dysfunction and failure. Furthermore, this provides a forum to begin the discussion on the cross-talk between sympathetic drive and proinflammatory cytokines and its determinant role in deleterious outcomes.

Keywords: Beta-adrenergic receptor; Cardiac hypertrophy and dilation; G-protein coupled receptor kinases; Heart failure; Interleukins; Tumor necrosis factor alpha.

Figure 1:

The schematic illustration describes the current understanding on the cross-regulation of pro-inflammatory cytokines and the neuro-hormonal-beta-adrenergic receptor (B-adrenergic receptors) axis. Cardiac stressors like changes in hemodynamic load or hypoxia leads to cardiac injury and in response pro-inflammatory cytokines including tumor necrosis factor α (TNFα) are employed as first step in the defense mechanism. This is followed by cardiac tissue repair and injury resolution phase primarily mediated by anti-inflammatory cytokines. However as TNFα inhibits B-adrenergic receptor function, it results in the inability of these receptors to respond to sympathetic drive fundamentally impeding cardiac responses to changes in mechanical demand. Reduced B-adrenergic receptor response leads to a feed-back increase in sympathetic hormones that in turn results in feed-forward elevation in pro-inflammatory cytokine TNFα which leads to self-perpetuating cycle that is now independent of pro- and anti-inflammatory response which was initiated due to injury. This cycle of increased TNFα now inhibits B-adrenergic receptors thereby, leading to feed-back and feed-forward cycle resulting in deleterious signaling mechanisms that underlies cardiac hypertrophy, deleterious remodeling and heart failure.