Abstract Body (Do not enter title and authors here): Background
The molecular mechanisms underlying colchicine’s benefits after myocardial infarction (MI) remain unclear. This study aimed to investigate the impact of colchicine on the plasma proteome.
Methods
Plasma samples were collected from a subset of 203 COLCOT trial participants at baseline and at six months. Proteomic profiling was performed using a targeted multiple-reaction monitoring mass spectrometry assay, while inflammatory biomarkers were quantified using electrochemiluminescence-based multiplex and enzyme-linked immunosorbent assays. The changes from baseline to six months were analyzed using analysis of covariance models adjusted for baseline values either using the original data or log-transformed data, depending on the distribution. The mean percentage reductions by colchicine are presented for in vitro assays and the logarithm of the ratio of LPS+colchicine/LPS were tested against zero.
Results
Reductions in the plasma concentrations of interleukin-12p70 (IL-12p70), IL-12/IL-23p40 (p40) subunit, IFN-γ, and IL-17A were observed in the colchicine group compared with the placebo group (adjusted geometric mean % changes of -42.8% vs. 0.4%, p = 0.007 for IL-12p70 and -23.7% vs. -4.1%, p = 0.053 for IFN-γ; adjusted mean changes of -12.8 pg/ml vs. 7.5 pg/ml, p = 0.003 for IL-12/IL-23p40 and -2.1 pg/ml vs. 0.2 pg/ml, p = 0.038 for IL-17A). Decreases over time in plasma IL-6 and IL-1α concentrations also occurred in the colchicine group compared with placebo (adjusted geometric mean % changes of -51.1% vs. -40.8%, p = 0.055 and -18.9% vs. 7.6%, p = 0.052, respectively). These effects were supported by in vitro assays that demonstrated colchicine-induced reductions of secretion of IL-12 (-41.8%, p=0.023), IL-23 (-21.0%, p=0.014) and IL-6 (-46.7%, p<0.001) by lipopolysaccharide-stimulated THP-1 macrophages. The proteomic panel showed that colchicine, compared with placebo, reduced additional inflammation-related biomarkers including alpha-1-acid glycoprotein, complement factor D and lysozyme C (adjusted geometric mean % changes of -35.6% vs. -28.1%, p = 0.026; -13.2% vs. -0.2%, p = 0.020; and -10.8% vs. -3.3%, p = 0.041, respectively).
Conclusions
Low-dose colchicine treatment after MI substantially reduced IL-12 and IL-23 signaling, suggesting important effects on Th1 and Th17 inflammatory pathways. The effects of colchicine on IL-6 and IL-1α also demonstrate its effects on NLRP3 inflammasome activity.