Dual-role protein RelB offers hope and caution for IBD drug development

Deep in the intestinal wall, tucked beyond where food is broken down and nutrients slip into the bloodstream, lie tiny immune outposts called solitary isolated lymphoid tissues. These structures house cells that decide how fiercely the gut should react to bacteria and other microbes. Strike the balance wrong and you get disease: too weak a response and pathogens colonize; too strong and the immune system turns on the gut itself, the defining feature of inflammatory bowel disease like Crohn's.

Researchers at the National Institute of Immunology in New Delhi have identified a protein called RelB as the fulcrum on which this balance tips. But their discovery, published in the Proceedings of the National Academy of Sciences, reveals something troubling: the same protein that protects the gut in one location actively harms it in another. This dual nature could complicate efforts to develop new treatments for inflammatory bowel disease, even as it opens unexpected doors.

The gut's immune defense system relies heavily on a signaling molecule called IL-23, which functions like an alarm that triggers inflammation to ward off threats. When IL-23 works properly, it sparks a chain reaction that activates antimicrobial defenses. But when IL-23 production spirals out of control, it drives chronic inflammatory diseases including inflammatory bowel disease and psoriasis. The researchers found that RelB acts as a gatekeeper for this entire system. It determines whether the gut can even produce the specialized dendritic cells that live in those immune outposts and manufacture IL-23. When the team engineered mice lacking RelB in these cells, the population of IL-23-producing dendritic cells nearly disappeared.

Soumen Basak, the immunologist who led the study, explained that earlier research had suggested RelB simply helped existing cells produce more IL-23. But faced with cells that were almost entirely absent, the team dug deeper. They tested two possibilities: either the loss of RelB reduced the number of these specialized dendritic cells, or it merely impaired their ability to produce IL-23. The evidence pointed decisively to the first explanation. RelB was required to build the protective army in the first place.

Yet RelB does not play the hero everywhere. While it constructs this defensive force in the intestinal wall, it simultaneously suppresses regulatory T-cells in nearby lymph nodes. These regulatory cells are the immune system's peacekeepers, the ones that calm inflammation. By shutting them down, RelB worsens chronic intestinal inflammation. The same protein, in different neighborhoods of the body, produces opposite effects.

The explanation may lie in the nature of dendritic cells themselves. These are not fixed entities with a single job. They are shapeshifters that adopt different identities depending on the tissue they inhabit and the chemical signals present there. RelB helps establish that local identity, a role that represents a significant conceptual shift in how scientists understand immune development. The researchers discovered that RelB activates a second protein called RBP-J, which acts as a key unlocking a different communication network. Only when this connection is complete can immature cells develop into the gut's specialized IL-23-producing sentinels. Two signaling systems long thought to operate independently actually cooperate to arm the gut.

But the paradox remains: how does a single protein act as a brake in one context and an accelerator in another? Alexander Hoffmann, a professor of immunology at UCLA, suggests the answer involves competition. RelB is a relatively weak activator compared to its cousin, RelA. When both proteins compete for access to the same gene, the weaker RelB blocks RelA's strong signal, effectively dialing down the overall effect so it appears to suppress. But on genes that RelA cannot reach, RelB's weak activation is sufficient to drive gene expression. The same protein, same mechanism, opposite outcomes depending on the genetic landscape.

Drugs that block IL-23 are already frontline treatments for inflammatory bowel disease, making RelB an intriguing but delicate potential target. Because the protein acts as both guardian and saboteur depending on its location, safely targeting it remains extraordinarily complex. Saurabh Mehandru, a gastroenterologist at Mount Sinai, notes that because this research used mice, the findings will need to be extended before they can be directly applied to patient care. He also points to a remaining gap: because the protective cells are almost entirely missing in the modified mice, it is unclear whether RelB is required to build those cells initially or simply to keep them alive once formed. Future experiments tracking cell lifespans will settle that question. Basak's team is already planning the next phase, investigating whether this relay operates at other vulnerable barriers like the lungs and whether manipulating it could yield new treatments.