About CCL17 / TARC:
Also known as thymus- and activation-regulation chemokine (TARC), CCL17 is a small cytokine that belongs to the CC chemokine family. While expressed primarily in the thymus, it also expressed transiently phytohemagglutinin-stimulated peripheral blood mononuclear cells. Here, we are going to look in detail at CCL17, it’s structure, function, mechanisms and interactions as far as current research shows.
Structure
Located on chromosome 16 in humans, alongside CCL22 and CX3CL1, the structures of the CC chemokine family can be notoriously hard to fully divine, but there has been some success in defining it using primarily molecular replacement. Using a search model based off of other chemokines like RANTES, proved unsuccessful, but other replacement programs like AmoRe, CNS, BEAST, and EPMR revealed more details of the structure. CCL17 forms dimers like RANTES and MCP1, made of 94 amino acids with a molecular mass of 10507 Da. CCL17 is hypothesized to exist in a “relaxed” or “tensed” state, based on whether or not the formation of an intermolecular bridge occurs between N terminals 8-12.
Function
CCL17 plays an important role, particularly as an inducting factor, of a range of diseases. In particular, it is closely related to inflammatory diseases like asthma, atherosclerosis, IBS, and other similar diseases. It serves as a chemotactic factor for T-lymphocytes but not monocytes or granulocytes. CCL17 has also been hypothesized to play a role in T-cell development in the thymus and the trafficking and activation of mature T-cells.
Mechanism
CCL17 is secreted by tumor-associated macrophages alongside other chemokines. These recruit Tregs to the tumor which function by dampening immune response. Without the appropriate Tregs, T-cells are produced without limitation, which can lead to further inflammation, autoimmune disease and eventual death. CCL22 production in HaCaT cells is dependent on ERK, EGFR, p38 MAPK, JNK, and JAK and is mediated by different signal pathways from those regulating CCL17 production. Meanwhile, production of CCL22 can be inhibited by PD98059, PD153035, Bay 11-7085, SB202190, c-Jun N-terminal kinase (JNK) inhibitor II, and Janus kinase (JAK) inhibitor 1. EGFR activation, on the other hand, enhances CCL22 production in cells while repressing CCL17.
Interactions
As mentioned, CCL17 production can be inhibited by PD98059, PD153035, Bay 11-7085, SB202190, c-Jun N-terminal kinase (JNK) inhibitor II, and Janus kinase (JAK) inhibitor 1 and repressed by CCL17. Furthermore, it binds with and induces chemotaxis in T cells, eliciting its effects by interacting with chemokine receptor CCR4. Th2 cytokine microenvironments in the skin are also hypothesized to increase CCL17 production, attracting Th2 cells in the skin and fractalkine shares signal sequence with CCL17.
With the difficult to pin nature of CCL17 (also known as TARC) and other members of the CC chemokine family, there is still ongoing research to learn more about the particulars of this cytokine. In particular, research continues as to the exact structure and interactions of CC17