What is the clinical evidence from this study?

Study design: Other. Population: Cardiac fibrosis. Intervention: Monocytes, neutrophils, IL-6, and MIF vs. HCF alone. Primary outcome: Collagen gel contraction, migration, and extracellular matrix deposition.

What question did this study set out to answer?

This research aims to uncover the mechanisms by which immune cells influence cardiac fibroblast activation and fibrosis.

May 16, 2026Open Access

Monocytes and neutrophils promote cardiac fibroblast pro-fibrotic phenotypes through IL-6 and MIF

Key Result

Monocytes and neutrophils, through the secretion of IL-6 and MIF, significantly promoted human cardiac fibroblast pro-fibrotic phenotypes including contractility, migration, and matrix deposition.

Key Points

This research aims to uncover the mechanisms by which immune cells influence cardiac fibroblast activation and fibrosis.
Used cell-derived matrices and collagen gels to study primary human cardiac fibroblast responses.
Conducted co-culture experiments with primary human cardiac fibroblasts and immune cells THP-1 and HL-60.
Analyzed cytokine levels and function blocking effects using recombinant proteins and antibodies.
Co-culture of fibroblasts with THP-1 and HL-60 cells increased collagen gel contraction (p<0.05).
MIF and IL-6 levels were significantly upregulated in co-cultures (p<0.01).
IL-6 neutralizing antibody reduced THP-1 induced fibroblast migration (p<0.05).

Structured PICO

Population

Primary human cardiac fibroblasts (HCF), THP-1 cells, HL-60 cells, primary human monocytes, and neutrophils

Intervention

Co-culture with immune cells or conditioned media; treatment with recombinant MIF and IL-6 or neutralizing antibodies

Comparator

HCF cultured alone (control)

Outcome

HCF pro-fibrotic response (collagen gel contraction and cell migration)surrogate

Early exposure of human cardiac fibroblasts to monocytes and neutrophils promotes pro-fibrotic phenotypes via IL-6 and MIF, identifying potential therapeutic targets to prevent adverse cardiac remodeling.

Limitations

Short-term exposure to immune cells may not recapitulate in vivo settings where immune cells persist and dynamically shift in phenotype.
The model does not account for the contributions of other cell types present in cardiac tissue.
Did not assess IL-6 and MIF contributions to early disease features in vivo.
Immune cell types were introduced in equal numbers, which may not fully reflect their physiological ratios in vivo.

Abstract

Cardiac fibrosis, characterized by activation of cardiac fibroblasts and accumulation of extracellular matrix (ECM), is associated with most cardiac pathological conditions, leading to adverse cardiac remodeling and accelerating progression of heart failure. Immune cell recruitment is a hallmark of early fibrosis; however, the underlying mechanisms linking early inflammation, fibroblast activation and perpetuation of cardiac fibrosis remain unclear. In this study, cell-derived matrices (CDM) and collagen gels were used to investigate primary human cardiac fibroblast (HCF) pro-fibrotic response, native ECM synthesis and interactions with immune cells. Direct co-culture of HCF with THP-1 and HL-60 cells, or conditioned media from HCF-immune cell co-cultures, resulted in enhanced HCF-induced contraction of collagen gels - a finding recapitulated using primary human monocytes and neutrophils. Pro-fibrotic cytokines, macrophage migration inhibitory factor (MIF) and interleukin-6 (IL-6), were upregulated in HCF-immune co-cultures and were further confirmed as active regulators of HCF contraction using recombinant purified cytokines and function blocking antibodies. Live imaging revealed that THP-1 cells increased HCF migration, which was suppressed by an IL-6 neutralizing antibody. These findings provide insight into the effects of early exposure of HCF to immune cells and shed light on early pro-fibrotic initiation mechanisms and therapeutic targets.

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