Tocilizumab does not ameliorate inflammation-induced left ventricular dysfunction in a collagen-induced arthritis rat
Ashmeetha Manilall1, Lebogang Mokotedi2, Sulè Gunter2
1School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 2193 Johannesburg, South Africa.
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.
