The Chemokine (C-C motif) ligand 18, or CCL18, is a protein that acts as a messenger to direct cellular traffic. It belongs to a family of proteins called chemokines, which are instrumental in guiding the movement of immune cells. Think of CCL18 as a recruitment signal, calling certain types of cells to specific locations. Under normal, healthy conditions, CCL18 helps manage the immune system’s daily operations, ensuring that cellular responses are appropriate and controlled.
The Biological Function of CCL18
CCL18 is primarily produced by antigen-presenting cells (APCs), which include dendritic cells and macrophages. These cells are scattered throughout the body’s tissues, where they stand guard, sampling their surroundings for signs of trouble. When APCs are activated, they begin to secrete CCL18, which then disperses into the surrounding area and bloodstream.
The main recipients of this message are naive T cells, which are T cells that have not yet encountered an antigen, or a foreign substance. CCL18 attracts these naive T cells, as well as other immune cells like B-cells and T-regulatory cells, to the location where the APCs first detected a signal. This migration brings the right immune components together to initiate a coordinated response.
The “C-C” in its classification refers to the protein’s structure, specifically the arrangement of two cysteine amino acids near one end of the molecule. This structural feature is common to a whole subfamily of chemokines and influences how the protein folds and interacts with its target cells. Identifying a direct counterpart in common laboratory animals like rodents has been difficult, making human-focused research important.
Under normal circumstances, CCL18 contributes to the body’s immune surveillance and helps maintain a non-aggressive, or tolerogenic, state. For instance, CCL18 produced by dendritic cells in lymph nodes can recruit naive B-cells, which are important for antibody production. It is also involved in generating T-helper 2 (Th2) type immune responses, associated with allergic reactions.
Connection to Fibrotic Diseases
The same signaling function that is beneficial in a healthy immune system can contribute to disease when it becomes dysregulated. In certain conditions, persistent overproduction of CCL18 leads to fibrosis, which is the formation of excessive scar tissue in an organ. This scarring process can stiffen tissues and impair their normal function.
In diseases like idiopathic pulmonary fibrosis (IPF), a debilitating lung condition, CCL18 levels are often significantly elevated. The chemokine is secreted in large amounts by M2 macrophages within the lung tissue. This abundance of CCL18 sends a powerful signal to fibroblasts, the cells responsible for producing collagen, stimulating them to ramp up production.
This mechanism leads to the progressive hardening and scarring of lung tissue, making it difficult for patients to breathe. A similar process occurs in scleroderma, a group of autoimmune diseases that cause hardening of the skin and connective tissues. In localized scleroderma, CCL18 expression is increased at the inflammatory edges of skin lesions, driving the fibrotic changes.
The chemokine’s role appears to be a direct driver of the fibrotic cascade, not just a side effect of the inflammation. Research has shown that the amount of CCL18 in affected tissues often correlates with the severity of the fibrosis. This highlights how a single signaling molecule can shift from a helpful regulator to a promoter of tissue damage.
The Role of CCL18 in Cancer
Beyond fibrosis, cancer cells can exploit the CCL18 signaling pathway to aid their growth and survival. In the tumor microenvironment, high levels of CCL18 can create conditions favorable for the cancer. This chemokine can be co-opted by tumors to help them spread to other parts of the body, a process called metastasis.
In certain cancers, such as breast and ovarian cancer, CCL18 enhances the ability of cancer cells to invade surrounding tissues and migrate to distant sites. For example, in breast cancer, CCL18 can bind to a receptor on cancer cells called PITPNM3. This triggers cellular changes that promote movement and invasion, guiding cancer cells as they break away from the primary tumor.
CCL18 can also help tumors evade the body’s immune system. It does this by attracting specific types of immune cells that suppress, rather than attack, the cancer. The chemokine recruits immunosuppressive cells, including regulatory T cells and M2-like macrophages, to the tumor site. These cells release signals that dampen the activity of cancer-fighting T-cells, creating a shield that protects the tumor.
Measuring CCL18 as a Biomarker
Given its direct involvement in fibrosis and cancer progression, CCL18 has emerged as a useful biomarker. A biomarker is a substance that can be measured in the body, such as in the blood, to provide information about a disease. Measuring CCL18 levels can offer insights into disease activity, prognosis, and response to treatment.
Elevated concentrations of CCL18 in the blood have been correlated with the severity of diseases like IPF and localized scleroderma. For patients with these conditions, tracking CCL18 levels can help clinicians assess how active the disease is. A decline in these levels following treatment can indicate that the therapy is successfully reducing the underlying disease process.
Measuring CCL18 is not used as a standalone tool for diagnosis; instead, it serves as a prognostic and monitoring marker. Interpreting these levels requires consideration of a patient’s full medical history, symptoms, and other diagnostic tests. The use of CCL18 as a biomarker is an active area of research, exploring its potential to predict disease relapse or guide therapeutic decisions.