> Skip repeated content

Revealing How Steroids Work

The Role of Transcriptional Coregulator GRIP1 in the Anti-inflammatory Actions of Glucocorticoids

HSS Authors:
Yurii Chinenov, PhD
Rebecca Gupte
Jana Dobrovolna, PhD
Jamie R. Flammer, PhD
Bill Liu
Francesco E. Michelassi
Inez Rogatsky, PhD

For decades, Glucocorticoid hormones (GC) have been used to control chronic inflammation in autoimmune disease. Known colloquially as "steroids", GC are potent suppressors of the immune system. While GC drug therapy is effective and relatively low cost, it comes with the downside of difficult and unwanted side-effects, both immediate and long-term.

Even though GC remain the most commonly prescribed class of medications worldwide, it has not been fully known, on a molecular level, precisely how steroids are able to block the cellular signaling that triggers inflammation. Now, a recent HSS study by Associate Scientist Inez Rogatsky, PhD, and her team, has revealed some key cellular mechanisms of how steroids work.

It Takes a GRIP for Steroids to Work

Dr. Rogatsky and her lab discovered that a particular protein called a Glucocorticoid hormone Receptor Interacting Protein-1 – or GRIP1 – may be responsible for how GC control inflammation.

Her team found that without GRIP1, the immune system’s inflammatory cells – called macrophages – just keep producing more and more pro-inflammatory proteins – called cytokines – that signal for increased inflammation. Without GRIP1, steroids fail to control inflammation.

Molecular Mechanisms

The team studied specially bred laboratory mice with macrophages that had no GRIP1. For control, these GRIP1-deficient mice were compared to an identical group of wild type mice who had intact GRIP1.

Samples of macrophages were taken from both kinds of mice and studied separately in cell cultures. Both mice and macrophages were treated with a chemical called lipopolysaccharide (LPS) that causes inflammation.

Cultured macrophages were administered LPS with or without specific doses of GC. In the wild type cultured macrophages, the steroids decreased inflammation. But when the GRIP1-deficient macrophages were given the same GC doses, inflammation did not stop.

In mice, LPS challenge causes a systemic inflammatory response which in high doses can lead to lethal LPS inflammatory shock. Normally, LPS challenge will trigger mice adrenal glands to produce their own natural GC to stop inflammation to prevent shock damage or death. Indeed, in the study, the wild-type mice survived the LPS challenge on their own.

However, the GRIP1-deficient mice all succumbed to inflammatory shock. Their own natural steroids were just as ineffective in stopping inflammation as the steroid drugs administered to their GRIP1-deficient macrophages in the cell cultures. 

Thus, the study showed GRIP1 was required for steroids to be effective. GRIP1-deficient macrophages continued producing more and more pro-inflammatory cytokines signaling for increased inflammation. Importantly, the study also uncovered the molecular mechanisms responsible.

GRIP1 Can Turn Genes On and Off

GRIP1 is a transcriptional coregulator, a specific kind of protein involved in transcribing genes into RNA that in turn gives rise to gene expression. Depending on the external stimulus, transcriptional coregulators will turn genes encoded by DNA in a given cell on and off.  This “on or off” regulates whether or not the genetic information inside that cell’s nucleus is transcribed.

There are hundreds of transcriptional coregulators in the body but basically they fall into two groups. Their names describe what each group does: coactivators activate gene transcription and corepressors repress it.

GRIP1 is a unique coregulator that can do both; it can promote transcription of some genes and halt transcription of others. The decision on which genes to regulate, and whether to activate or repress transcription, depends on which particular protein – called a DNA-binding transcription factor – brings GRIP1 to the cell’s DNA. 

GRIP1 Required to Halt Cytokine Gene Transcription

One such DNA-binding transcription factor is called NFkB (short for nuclear factor kappa-light-chain-enhancer of activated B cells). In a normal immune response, NFkB stimulates macrophages to produce pro-inflammatory cytokines. NFkB does this by directly binding genes that code for pro-inflammatory cytokines and activates their transcription, so more cytokines are produced. More transcription, more cytokine production, more inflammation.

Steroids, both natural and synthetic, can stop NFkB from activating transcription of pro-inflammatory cytokine genes, which shuts down the production of inflammatory cytokines. What happens, is the GC receptors on macrophages recognize the GC and the steroids go to work. The steroid-bound GC receptors then bind NFkB, which represses NFkB’s transcriptional activity. Less transcription, less cytokine production, less signals for inflammation.

What the HSS study discovered, is that without GRIP1, the GC receptors on macrophages fail to repress NFkB activity. Transcription is ‘on’, pro-inflammatory cytokines keep being produced, and chronic inflammation continues. Without GRIP1, steroids don’t stop inflammation.

New Studies, New Targets for Therapies

The more that can be discovered about the complexities of how GC work on a cellular level, the more possibilities exist to tailor individual patient treatments, and eventually develop new drugs, or new combinations of therapies, that harness GC’s power to reduce inflammation without the unwanted side effects.

Now that the HSS study has revealed a new piece of the puzzle of how steroids work, further studies can explore how GRIP1 might be used to regulate NFkB function with lower doses of steroids, or design novel more selective GC-like drugs that are able to suppress inflammation while causing less side effects. Discoveries made in this new HSS study can help advance that process.

Study published in the Proceedings of the National Academy of Sciences of the United States of America, July, 2012

HSS Authors:
Yurii Chinenov, PhD
Rebecca Gupte
Jana Dobrovolna, PhD
Jamie R. Flammer, PhD
Bill Liu
Francesco E. Michelassi
Inez Rogatsky, PhD


Need Help Finding a Physician?

Call us toll-free at:

Related Professional Content

Departments and Services

Conditions & Treatments

adult child
Select A Body Part
Conditions: Adult head Conditions: Adult spine Conditions: Adult shoulder Conditions: Adult elbow Conditions: Adult hand Conditions: Adult hip Conditions: Adult knee Conditions: Adult ankle Conditions: Adult head Conditions: Adult full body Conditions: Child spine Conditions: Child elbow Conditions: Child hip Conditions: Child hand Conditions: Child knee Conditions: Child ankle Conditions: Child full body

Conditions A-Z