Research Highlights

Alternative switch triggers different immune pathway

Published online 31 March 2020

Analyses reveal a new binding site that sheds light on our immune responses to infections.

Letizia Diamante

Scientists have uncovered an alternative mechanism, triggered by an immune cell receptor, for activating the release of pro-inflammatory proteins during infection. The finding adds to understanding about the immune response and could help the development of drugs that fine-tune it. 

When the TLR4 membrane receptor on microbe-eating macrophages comes into contact with bacteria, it triggers one of two known pathways. In one pathway, pro-inflammatory proteins called cytokines, such as tumour necrosis factor alpha, interleukin-1 beta, interleukin-6 and interleukin-12p40, are released. In the other pathway, activated TLR4 is internalised by the macrophage, releasing an immune protein called interferon beta, which activates the attachment of a phosphate group to a gene-regulating protein called STAT1. This in turn leads to the production of a distinct subset of immune proteins. 

A team led by Osaka University researchers in Japan, including a collaborator at Al-Hussein Bin Talal University, Jordan, has now found a new binding site on STAT1 for phosphate group attachment. When this alternative site is phosphorylated following TLR4 internalisation, STAT1 attaches to DNA sites on two distinct genes, leading to the sustained release of interleukin-6 and interleukin-12p40.

“We know that cytokines are produced in response to surface TLR4 stimulation,” explains Osaka University’s Hozaifa Metwally. “Our work shows that these same cytokines can also be produced after TLR4 internalisation.”

“Understanding how this alternative phosphorylation occurs in macrophages, and finding out whether it occurs in other cells, can help scientists more specifically target the production of pro-inflammatory cytokines according to our needs,” says Osaka University immunologist, Tadamitsu Kishimoto. For example, developing drugs that enhance the phosphorylation of this alternative binding site on STAT1 could result in more production of interleukin-6 and interleukin-12p40, at the expense of tumour necrosis factor alpha and interleukin-1 beta, and vice versa, explains Kishimoto.

Further studies could lead to the development of adjuvants that can be added to vaccines to fine-tune the immune response.


Metwally, H. et al. Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production. Sci. Signal. 13, eaay0574 (2020).