How Mushrooms Balance Pro- and Anti-Inflammatory Cytokines

Mushrooms & Cytokine Modulation

Both directions

The same shiitake mushroom contains β-glucan fractions that activate immune responses AND others that suppress pro-inflammatory cytokines, depending on which fraction, at what dose, and in what immune context.

Murphy et al., Science of the Total Environment, 2020

52 adults

in Dai 2015 RCT: daily shiitake for 4 weeks improved immune cell proliferation and cytokine production in healthy adults

Bidirectional

mushrooms can activate underfiring immunity OR suppress overactive inflammation via different compound fractions

Synergistic

reishi + shiitake + maitake combination showed cytokine modulation greater than any species alone (Tangen 2019)

Murphy et al., Science of the Total Environment, 2020

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Mushrooms are sold as "immune-boosting" supplements. They are also marketed as "anti-inflammatory" agents. A reasonable question: can something simultaneously strengthen immune activity and reduce inflammation? These sound like opposite effects, and the apparent contradiction trips up a lot of explanations of how medicinal mushrooms work.

The answer requires distinguishing between two very different immune functions: the ability to mount a response when one is needed, and the ability to contain a response once it has been mounted. A 2020 study by Murphy and colleagues provides the most precise illustration of how mushrooms can do both.^[1] They isolated different beta-glucan fractions from the same shiitake mushroom and tested each one. The fractions produced different immunomodulatory effects, with some activating immune responses and others suppressing pro-inflammatory cytokines. One mushroom. Multiple fractions. Opposing effects. This is the mechanistic basis of immunomodulation, and it is what most descriptions of "immune-boosting mushrooms" fail to explain. For the broader foundation of mushroom anti-inflammatory mechanisms, see How Mushrooms Fight Inflammation: NF-kB, COX-2, and Beyond.

What Cytokines Are and Why Balance Is the Actual Goal

Before explaining how mushrooms interact with the cytokine system, the system itself needs a brief explanation. Cytokines are small signaling proteins produced by immune cells that coordinate the immune response. They are not individually good or bad; they are regulatory messages that need to be appropriate in type, timing, and magnitude.

Pro-inflammatory cytokines, primarily TNF-alpha, IL-6, and IL-1beta, drive the inflammatory response. When the immune system detects infection or tissue damage, these cytokines tell immune cells to mobilize, increase blood flow to the affected area, elevate body temperature, and attack pathogens. Without them, infections cannot be cleared. With too much of them, persisting for too long, they cause the collateral tissue damage associated with chronic inflammatory diseases: rheumatoid arthritis, inflammatory bowel disease, metabolic syndrome, and atherosclerosis.

Anti-inflammatory cytokines, primarily IL-10 and TGF-beta, act as brakes on the inflammatory response. They suppress immune cell activation, reduce pro-inflammatory cytokine production, and help resolve inflammation once the immediate threat is gone. Too little anti-inflammatory signaling and inflammation becomes self-perpetuating; too much and the immune system cannot clear infections efficiently.

The goal is not maximally activating or maximally suppressing cytokines. The goal is the appropriate response to each situation: activating when under-stimulated (chronic immune suppression from stress, age, or disease), suppressing when over-activated (chronic inflammation from injury, infection, or autoimmune dysregulation). Mushrooms interact with this system through multiple compound classes, and the effect depends on which compound, in which immune context.

The Murphy 2020 Finding: One Mushroom, Multiple Cytokine Profiles

Murphy and colleagues' 2020 study is the clearest demonstration of how a single mushroom species can produce different and opposing immune effects depending on which fraction is used.^[1] They extracted multiple beta-glucan fractions from shiitake (Lentinula edodes) and tested each fraction's immunomodulatory activity in cell culture systems.

The key finding: different beta-glucan fractions from the same mushroom produced measurably different immunomodulatory profiles. Some fractions activated pro-inflammatory pathways. Others showed cytokine-suppressing and pulmonary cytoprotective effects. The authors specifically discussed the COVID-19 cytokine storm implications, since the same mushroom that could support immune activation also contained fractions relevant to excessive inflammatory responses.

This result directly explains the apparent paradox. "Shiitake extract" is not one compound with one effect. It is a mixture of polysaccharide and other compounds with different molecular structures, different receptor targets, and different downstream effects on cytokine production. An extract heavy in one fraction will behave differently from an extract heavy in another fraction, even from the same mushroom batch.

The practical consequence for interpreting mushroom research: any study that uses an uncharacterized mushroom extract and measures immune outcomes is studying the net effect of multiple competing compound activities. A study showing "immune activation" from mushrooms and a study showing "cytokine suppression" from mushrooms might both be correct, using different extracts or different fractions from the same species.

The Human Evidence for Immune Activation

The strongest human evidence for mushroom-driven immune activation comes from Dai and colleagues' 2015 randomized dietary intervention.^[3] Fifty-two healthy young adults ate whole dried shiitake mushrooms daily for four weeks. At the end of the four weeks, researchers measured immune cell parameters including natural killer (NK) cell activation, T cell proliferation, secretory IgA (a marker of mucosal immune function), and cytokine production capacity.

The results showed improvements across multiple immune parameters. NK cell function improved, indicating better innate immune surveillance. T cell proliferation rates were higher, suggesting improved adaptive immune capacity. Secretory IgA levels increased, suggesting enhanced mucosal immunity. CRP (C-reactive protein, an inflammation marker) did not increase. The immune activation happened without driving systemic inflammatory signaling upward.

This is the key point: immune activation that occurs without elevated inflammation markers is not the same as inflammation. The body's immune surveillance capacity improved without triggering the pro-inflammatory cytokine cascade that causes tissue damage. This is the distinction between "immunostimulatory" and "pro-inflammatory" that most supplement marketing conflates.

Lima and colleagues' 2012 randomized clinical trial in elderly women using Agaricus blazei Murrill supplementation measured inflammatory mediators and provides a second data point from a different species and population.^[4] The elderly population is particularly relevant because age is associated with two simultaneous immune problems: reduced immune surveillance capacity (immunosenescence) and elevated chronic baseline inflammation (inflammaging). The study measured effects on both aspects.

The Human Evidence for Anti-Inflammatory Effects

Against this activation evidence, the evidence for cytokine suppression sits in a different experimental context. Dudhgaonkar and colleagues' 2009 study isolated triterpenes from Ganoderma lucidum (reishi) and tested them against LPS-stimulated (lipopolysaccharide, a bacterial component that triggers an inflammatory response) macrophages in vitro and against endotoxemic mice in vivo.^[7] TNF-alpha and IL-6 secretion were markedly suppressed by the triterpenes in both models.

The LPS-stimulation context is critical. These experiments measured triterpene effects against an already-triggered inflammatory response. This is not inhibiting normal immune function; it is suppressing excessive cytokine output in tissues that are already inflamed beyond what is needed for defense.

Jedinak and colleagues' 2011 research on oyster mushroom (Pleurotus ostreatus) extract found that it inhibited NF-kB and AP-1 signaling in macrophages, reducing TNF-alpha, IL-6, and other pro-inflammatory cytokines.^[6] What makes this result notable for consumers is the species: oyster mushroom is one of the most widely available and inexpensive culinary mushrooms, not an exotic medicinal species. This suggests that the cytokine-modulating effects of mushrooms are not exclusive to medicinal species.

Why the Same Mushroom Can Do Both: Compound and Context

The resolution of the apparent paradox comes from two variables: which compound is acting, and what immune state it is acting upon.

Guggenheim and colleagues' 2014 review of immune modulation across five major mushrooms provides the species-level context.^[2] Each species (reishi, shiitake, maitake, turkey tail, and chaga) modulates cytokines through different compound classes and via different receptor pathways. Reishi's dominant immune-relevant compounds are triterpenes (ganoderic acids) that suppress pro-inflammatory signaling via NF-kB inhibition. Shiitake's dominant immune-active compounds are beta-glucan polysaccharides that activate macrophages and NK cells via dectin-1 and TLR receptors. These are mechanistically opposite effects from different molecular classes.

Within a single species, as Murphy 2020 demonstrated, even the same compound class (beta-glucans) can produce different effects when the structural sub-fractions differ.^[1] The beta-glucan that activates dectin-1 on macrophages and the beta-glucan that suppresses pro-inflammatory cytokine release are not the same molecule. They share a general structural category but have different backbones, branching patterns, and molecular weights that determine their receptor interactions.

The immune state context adds a second layer. A macrophage that is already maximally activated by LPS (as in the Dudhgaonkar experiments) responds to triterpenes differently than a resting macrophage in a healthy adult (as in the Dai dietary study). The same compound applied to different immune states can produce different net effects. This is not a contradiction in the research. It is how most pharmacological agents work: dose, context, and baseline state determine response.

What Combination Evidence Adds

Tangen and colleagues' 2019 study tested the immunomodulatory effects of a combination formulation containing reishi, shiitake, and maitake on human macrophages.^[5] The combination produced synergistic effects on cytokine modulation that exceeded what any single species produced alone. The implication: combining species with complementary compound profiles (triterpenes from reishi + polysaccharides from shiitake and maitake) may produce a more complete immunomodulatory response than any single-species extract.

This is an in vitro finding, and extrapolating it to oral supplementation requires caution about bioavailability and absorption. But it provides a mechanistic rationale for why multi-species formulations are used in traditional medicine systems: different species contribute different compound classes that address different aspects of immune regulation.

For more on the specific cytokine targets and suppression data, see Mushrooms and TNF-Alpha: Reducing the Master Inflammatory Signal, Mushroom Compounds and IL-6 Reduction, and Mushroom Triterpenes and TNF-Alpha Suppression: Quantifying Anti-Inflammatory Potency. For the acute immune overreaction angle including cytokine storm, see The Cytokine Storm: Can Mushrooms Help Modulate Immune Overreaction?. For cross-links to species-specific data, see Lion's Mane and Anti-Inflammatory Cytokines: The Mood-Inflammation Link.

The Bottom Line

Medicinal mushrooms are both immune-activating and anti-inflammatory because different compound fractions within the same mushroom act through different pathways and produce different effects depending on which immune state they encounter. Murphy 2020 demonstrated this concretely: different beta-glucan fractions from the same shiitake mushroom produced opposing immune effects. The Dai 2015 RCT confirmed immune cell activation in healthy adults from daily shiitake consumption; the Dudhgaonkar 2009 study confirmed TNF-alpha and IL-6 suppression by reishi triterpenes in inflammatory conditions. The mechanism is not contradiction but bidirectional regulation: polysaccharides tend toward activation, triterpenes tend toward suppression, and the net effect depends on which fractions are present, at what dose, in what immune context.

Frequently Asked Questions

Do mushrooms stimulate or suppress the immune system?

Both, depending on which compounds are present and what immune state they are acting on. Murphy et al. 2020 showed that different beta-glucan fractions from the same shiitake mushroom produced different immunomodulatory effects: some activating, some suppressing. Beta-glucan polysaccharides tend to activate macrophages and NK cells via dectin-1 and TLR receptors. Triterpenes from reishi and Antrodia tend to suppress overactive pro-inflammatory cytokines like TNF-alpha and IL-6 via NF-kB pathway inhibition. The net effect of any mushroom product depends on its compound composition.

How can something be both anti-inflammatory and immune-boosting?

Because inflammation and immune function are distinct processes that can be independently regulated. Immune function refers to the ability to recognize and respond to pathogens, activate NK cells, and generate antibodies. Inflammation refers to the intensity and duration of the cytokine response, which can persist and cause damage after a threat is gone. Mushrooms can improve immune surveillance capacity (activate appropriate responses when needed) while also suppressing chronic or excessive cytokine production (reduce inflammatory cytokines that damage tissue when overproduced). The Dai 2015 RCT showed immune activation without elevated inflammation markers in healthy adults, demonstrating this distinction.

What does cytokine balance mean?

Cytokine balance refers to the ratio between pro-inflammatory cytokines (like TNF-alpha, IL-6, and IL-1beta, which drive inflammation) and anti-inflammatory cytokines (like IL-10 and TGF-beta, which suppress immune responses). Healthy immune function requires both: pro-inflammatory cytokines to fight infections, and anti-inflammatory cytokines to resolve inflammation and prevent tissue damage. Imbalance toward pro-inflammatory signaling leads to chronic inflammatory diseases. Imbalance toward anti-inflammatory dominance leads to immune suppression and poor infection clearance. Mushrooms are described as immunomodulators because they appear to push the balance in the appropriate direction for the immune state they encounter.

Can mushrooms make inflammation worse?

The research does not support mushrooms generally worsening inflammation in people with normal immune function. However, the immune-activating fraction of mushroom compounds (beta-glucan polysaccharides that stimulate macrophage and NK cell activity) could theoretically increase inflammatory cytokine production in someone whose immune system is already in a state of excessive activation. This is a theoretical concern, not a documented clinical problem from dietary mushroom consumption, but it is the mechanism that makes the "immune-boosting" framing potentially overly simple. The Murphy 2020 study explicitly showed that different fractions from the same mushroom can have opposing effects, which is why characterizing any mushroom extract as uniformly pro- or anti-inflammatory is an oversimplification.

What is immunomodulation?

Immunomodulation means altering the activity of the immune system in a context-appropriate way, rather than simply activating it more or less. A true immunomodulator can activate immune function when it is insufficient and suppress it when it is excessive, depending on the signals it receives from the immune state of the cells it encounters. Mushrooms are often described as immunomodulators because different compound fractions regulate different immune pathways in different directions. The Guggenheim 2014 review of five major mushrooms confirmed that each species modulates cytokines through different compound classes and pathways, producing different net effects on different immune cell populations.

Sources & References

1. 1RTHM-00638·Murphy, Emma J et al. (2020). “β-Glucan extracts from the same edible shiitake mushroom Lentinus edodes produce differential in-vitro immunomodulatory and pulmonary cytoprotective effects - Implications for coronavirus disease (COVID-19) immunotherapies..” The Science of the total environment.Study breakdown →PubMed →↩
2. 2RTHM-00323·Guggenheim, Alena G et al. (2014). “Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology..” Integrative medicine (Encinitas.Study breakdown →PubMed →↩
3. 3RTHM-00368·Dai, Xiaoshuang et al. (2015). “Consuming Lentinula edodes (Shiitake) Mushrooms Daily Improves Human Immunity: A Randomized Dietary Intervention in Healthy Young Adults..” Journal of the American College of Nutrition.Study breakdown →PubMed →↩
4. 4RTHM-00254·Lima, C U J O et al. (2012). “Agaricus blazei Murrill and inflammatory mediators in elderly women: a randomized clinical trial..” Scandinavian journal of immunology.Study breakdown →PubMed →↩
5. 5. Source details for this reference are not yet available.
6. 6RTHM-00219·Jedinak, Andrej et al. (2011). “Anti-inflammatory activity of edible oyster mushroom is mediated through the inhibition of NF-κB and AP-1 signaling..” Nutrition journal.Study breakdown →PubMed →↩
7. 7RTHM-00152·Dudhgaonkar, Shailesh et al. (2009). “Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum..” International immunopharmacology.Study breakdown →PubMed →↩