Tocilizumab does not ameliorate inflammation-induced left ventricular dysfunction in a collagen-induced arthritis rat model

Abstract

Background

Interleukin-6 (IL-6) is an attractive therapeutic target due to its diverse roles in the pathogenesis of conditions characterized by systemic inflammation. IL-6 has also been implicated in the pathophysiology of heart failure. This study aimed to investigate the impact of IL-6 receptor blockade with tocilizumab on the molecular pathways underlying systemic inflammation-induced left ventricular (LV) dysfunction in a collagen-induced arthritis (CIA) rat model.

Methods

Seventy-three Sprague-Dawley rats were divided into three groups: control (n=28), CIA (n=29), and CIA+IL-6 blocker (n=16). Inflammation was induced in the CIA and CIA+IL-6 blocker groups using bovine type II collagen emulsified in incomplete Freund's adjuvant. After arthritis onset, the CIA+IL-6 blocker group received tocilizumab for six weeks. Circulating inflammatory markers, relative LV mRNA gene expressions, and LV systolic and diastolic function were assessed.

Results

CIA rats developed LV diastolic and early-stage LV systolic dysfunction, which was not ameliorated by IL-6 blocker administration (p > 0.05). IL-6 blocker administration did not impact circulating inflammatory markers (all p > 0.05) or LV mRNA expression of inflammatory markers compared to the CIA group, nor did it reverse inflammation-induced increases in LV mRNA expression of genes involved in fibrosis and collagen turnover, regulation of titin phosphorylation, Ca²⁺ handling, mitochondrial function, or apoptosis (all p > 0.05). However, LV mRNA expressions of CD68 and LOX, genes involved in macrophage infiltration and collagen cross-linking, were increased in the CIA group (p = 0.03, p = 0.0004), but not in the CIA+IL-6 blocker group compared to controls (p > 0.05).

Conclusion

These results suggest that although IL-6 blockade by tocilizumab may prevent inflammation-induced collagen cross-linking, the current treatment regimen may not protect against inflammation-induced LV dysfunction. Therefore, the role of IL-6 in the molecular mechanisms of inflammation-induced LV dysfunction remains inconclusive.