Mitogen-activated protein kinases, or MAPKs, are a family of signaling enzymes that operate inside virtually every cell of the body. When a cell receives an external cue, such as a stress signal, a cytokine, or an antigen encounter, these kinases relay the message from the cell surface to the nucleus by a chain reaction of phosphorylation events. The family includes three major branches: p38, which is strongly associated with inflammation and cellular stress responses; extracellular signal-regulated kinase (ERK), which typically drives proliferation and differentiation; and c-Jun N-terminal kinase (JNK), which responds to stress and can trigger programmed cell death. Because immune cells rely heavily on these cascades to orchestrate their activation and effector functions, researchers have long suspected that MAPK signaling might be disturbed in autoimmune diseases, including those affecting the peripheral nerves.

The Belgrade team, led by Marina Stamenkovic and Irena Vukovic as co-first authors under the supervision of Vladimir Trajkovic and Verica Paunovic, went beyond the MAPK family to examine a broader metabolic network. They also measured the activity of AMP-activated protein kinase (AMPK), an intracellular energy sensor that switches cells into conservation mode when fuel is scarce, and mechanistic target of rapamycin complex 1 (mTORC1), the master growth regulator that AMPK antagonizes. Together, these pathways govern autophagy, the cellular recycling process by which cells digest their own damaged components. Autophagy has emerged in recent years as a critical regulator of immune cell behavior, and earlier work by some of the same investigators had linked reduced AMPK signaling in blood mononuclear cells to the severity of Guillain-Barré syndrome, another immune-mediated neuropathy.

To test whether these pathways are altered in chronic immune neuropathies, the researchers collected peripheral blood mononuclear cells, the mixed population of lymphocytes and monocytes that circulates in the bloodstream, from 17 patients with CIDP who had not yet received any immunotherapy, and from 7 patients with MMN who were already on chronic maintenance therapy with intravenous immunoglobulin (IVIg). They compared these samples with cells from age- and sex-matched healthy controls, using immunoblotting, a laboratory technique that separates proteins by molecular weight and detects them with specific antibodies, to quantify the phosphorylated, active forms of the signaling enzymes as well as markers of autophagy flux.

The results were strikingly selective. In both CIDP and MMN patients, the levels of phosphorylated, active p38 MAPK in circulating mononuclear cells were significantly higher than in healthy controls. In contrast, the activity of ERK and JNK, the other two MAPK branches, was not significantly altered, and neither were the AMPK/mTORC1 metabolic axis nor the autophagy markers. This specificity matters because it suggests that p38 activation is not a nonspecific consequence of chronic illness or inflammation but a distinctive feature shared by these two related yet clinically distinct neuropathies. The finding also aligns with earlier animal studies in which p38 and other MAPKs were found to be activated in the sciatic nerves of rats with experimental autoimmune neuritis, the laboratory model of human immune-mediated demyelinating neuropathy.

Perhaps the most intriguing clinical correlation emerged from the MMN group. The amount of p38 MAPK protein in patients’ blood cells was negatively correlated with their muscle strength, meaning that patients with more of this kinase in their leukocytes tended to have weaker muscles. Notably, this correlation was absent in CIDP, hinting that p38 may track disease activity differently in the two conditions. MMN is characterized by purely motor deficits, often beginning in the hands, and muscle strength is the principal measure by which clinicians judge disease progression and treatment response. A blood-based molecular correlate of strength, if confirmed, could eventually complement the clinical scales and electrophysiological tests currently used to monitor these patients.

The therapeutic dimension of the study came from comparing patients before and after IVIg treatment. Intravenous immunoglobulin is a pooled preparation of antibodies harvested from thousands of healthy donors, and it is a mainstay of therapy for both CIDP and MMN, though the two diseases differ in their longer-term management. Among nine CIDP patients who received IVIg, the treatment did not change the phosphorylation status of AMPK, any of the MAPKs, or the autophagy markers in their blood cells. Among six MMN patients, however, IVIg produced a measurable biochemical effect: it reduced the phosphorylation of p38 MAPK, ERK, and AMPK in their mononuclear cells. Crucially, the magnitude of the drop in phospho-p38 levels correlated with the improvement in hand grip strength, directly linking a molecular change in circulating immune cells to a functional clinical outcome.

These divergent responses raise fascinating questions about how IVIg works and why the same therapy might engage different mechanisms in different diseases. Previous research has shown that IVIg can suppress inflammatory signaling in monocytes, including NF-κB and p38 MAPK activation driven by tumor necrosis factor-alpha, and can induce autophagy in peripheral blood mononuclear cells. The new findings are consistent with the idea that in MMN, IVIg dampens a p38-centered inflammatory program in leukocytes, and that this immunological cooling accompanies, and may contribute to, the recovery of motor function. In CIDP, by contrast, the lack of detectable signaling change suggests either that IVIg acts through mechanisms not captured by these particular readouts, or that the relevant immune events occur in tissue-resident cells rather than in the circulating pool sampled by the researchers.

The authors are careful to frame the study as exploratory, and the limitations are real. The patient cohorts are small, particularly the MMN group, and the CIDP patients were treatment-naïve while the MMN patients were already on therapy, an asymmetry that complicates direct comparison between the diseases. Immunoblotting of bulk mononuclear cells also averages signals across heterogeneous cell populations, so the p38 elevation could reflect changes in a specific subset of lymphocytes or monocytes rather than a uniform shift. Nevertheless, the correlation between phospho-p38 reduction and grip strength improvement in MMN provides a concrete, testable hypothesis for future studies with larger cohorts and longitudinal sampling.

The findings also carry translational promise. Pharmacological inhibitors of p38 MAPK have been developed for decades, and one such inhibitor, losmapimod, recently showed encouraging results in a phase 2b trial for facioscapulohumeral muscular dystrophy, demonstrating that p38 blockade can be pursued safely in neuromuscular disease. The safety concerns that have historically shadowed p38 inhibitors, including effects on liver function and stress responses, remain relevant, but a circulating biomarker that identifies which patients are most likely to benefit could transform trial design. For now, the study’s central message is that a single stress-activated kinase in blood cells may serve as both a window into disease activity and a readout of therapeutic response in multifocal motor neuropathy, offering researchers a molecular thread to follow in the search for more precise treatments for these rare, disabling conditions.

Subject of Research: The role of leukocyte p38 MAP kinase signaling in immune-mediated peripheral polyneuropathies and its modulation by intravenous immunoglobulin therapy

Article Title: The role of leukocyte p38 MAP kinase in immune-mediated peripheral polyneuropathies: distinct modulation by intravenous immunoglobulins

Article References: Stamenkovic, M., Vukovic, I., Milosevic, E., Peric, S., Paunic, A., Anicin, A., Basta, I., Bozovic, I., Palibrk, A., Ivanovic, V., Trajkovic, V., & Paunovic, V. (2026). The role of leukocyte p38 MAP kinase in immune-mediated peripheral polyneuropathies: distinct modulation by intravenous immunoglobulins. Journal of Neurology, 273(10), Article 627. https://doi.org/10.1007/s00415-026-14106-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14106-3

Keywords: p38 MAPK, CIDP, multifocal motor neuropathy, intravenous immunoglobulin, peripheral neuropathy, immune cell signaling, AMPK, mTORC1, autophagy, ERK, JNK, biomarker

The sympathetic nervous system, the body’s fight-or-flight machinery, communicates with tissues through neurotransmitters such as norepinephrine, which bind to adrenergic receptors on cell surfaces. The predominant subtype in many tissues is the beta-2 adrenoceptor, a G protein-coupled receptor that triggers cascades of intracellular messengers when activated. Epidemiological and experimental work over the past two decades has implicated this pathway in cancer progression, with studies showing that beta-blocker drugs can reduce secondary tumor formation in breast cancer patients and that sympathetic activation can induce a metastatic switch in primary breast tumors. What has been missing is a precise account of how this signaling intersects with hormone receptor biology inside tumor cells themselves.

To dissect that intersection, the team turned to two of the most widely used breast cancer cell lines in laboratory research: MCF-7 cells, which are estrogen receptor positive, and MDA-MB-231 cells, which lack the estrogen receptor. Both were grown in vitro and treated with terbutaline, a selective beta-2 adrenoceptor agonist, at two concentrations spanning a physiological range, and with propranolol, a non-selective beta-adrenergic antagonist, to test whether observed effects could be blocked. The researchers then measured a battery of outcomes: cell cycle progression as a readout of proliferation, levels of the pro-angiogenic factors VEGF-A and VEGF-C by enzyme-linked immunosorbent assay, activation of the ERK and CREB signaling proteins, nitric oxide production via the Griess assay, and expression of two cancer-associated microRNAs, miR-21 and miR-191, by quantitative PCR.

The results were strikingly divergent. In the estrogen receptor positive MCF-7 cells, terbutaline acted as an accelerant: it enhanced proliferation, boosted VEGF-C expression, raised miR-191 levels, and strengthened ERK phosphorylation, the activated form of the signaling protein. In the estrogen receptor negative MDA-MB-231 cells, the very same drug produced the opposite effect on every one of those measures, attenuating proliferation, VEGF-C output, miR-191 expression, and p-ERK signaling. In other words, a single receptor, engaged by a single ligand, pushed the two cell types in opposite biological directions, with the estrogen receptor status of the cell acting as the molecular switch that determined which way the machinery would turn.

Not everything split along receptor lines, however, and those exceptions proved equally informative. CREB phosphorylation, a second major signaling arm downstream of beta-2 adrenoceptors, was enhanced in both cell lines regardless of estrogen receptor status. VEGF-A, the canonical driver of blood vessel growth, was downregulated in both. Nitric oxide production and miR-21 expression both increased in an estrogen receptor independent fashion. These findings suggest that while the divergent outcomes in proliferation and VEGF-C regulation likely arise from selective engagement of ERK-dependent pathways shaped by estrogen receptor crosstalk, some beta-adrenergic effects operate through mechanisms that bypass the estrogen receptor entirely, underscoring the layered complexity of adrenergic signaling in breast cancer.

The microRNA data add an epigenetic dimension to the story. miR-191, which tracked precisely with the opposing proliferative responses, is a recognized player in breast cancer biology, and prior work has shown that estrogen can activate the miR-191/425 cluster in a manner that depends on estrogen receptor status. miR-21, by contrast, rose in both cell lines after terbutaline treatment, consistent with its reputation as a broadly expressed oncomir associated with multiple breast cancer subtypes. The finding that adrenergic stimulation can tune these regulatory RNAs differently depending on hormone receptor context hints that stress hormones may reshape the epigenetic landscape of tumors in a subtype-specific way.

Propranolol provided the pharmacological counterpoint. The beta-blocker significantly attenuated the terbutaline-induced effects in both cell lines, confirming that the observed changes were genuinely mediated through beta-adrenergic receptors rather than off-target actions of the agonist. Notably, the magnitude of inhibition was greater in the estrogen receptor positive cells, reinforcing the conclusion that this subtype is more exquisitely dependent on adrenergic input for the signaling responses measured. This detail carries potential clinical resonance, because it aligns with retrospective observations that beta-blocker therapy is associated with improved cancer-specific survival in breast cancer patients, and raises the possibility that patients with hormone receptor positive tumors might derive particular benefit.

The study builds on the same group’s earlier demonstration that estrogen receptor status governs how alpha-1 and alpha-2 adrenoceptors regulate cell survival and angiogenesis in breast cancer lines, and on work showing that estrogen modulates beta-2 adrenoceptor responses in immune cells through distinct intracellular pathways. Together, these findings sketch a picture in which the tumor’s hormonal identity rewires how it interprets nervous system signals. Mechanistically, the authors propose that estrogen receptor crosstalk selectively channels beta-2 adrenoceptor signaling into ERK-dependent versus CREB-dependent branches, producing the divergent proliferative and angiogenic outcomes, while parallel estrogen receptor independent routes account for the shared changes in nitric oxide, miR-21, VEGF-A, and CREB.

The implications cut in several directions. For researchers, the work is a caution against treating breast cancer as a single entity in stress-biology experiments: pooling estrogen receptor positive and negative models could average away effects that are real and opposite in each subtype. For clinicians, it adds mechanistic weight to the idea that beta-adrenergic signaling is a modifiable driver of tumor behavior, and suggests that estrogen receptor status might one day serve as a biomarker for selecting patients most likely to benefit from beta-blocker repurposing. For patients, it offers a tangible molecular account of how chronic stress physiology could influence tumor growth, at least for hormone-sensitive disease.

Important caveats remain. The findings come from cell lines in culture, where the tumor microenvironment, immune cells, vasculature, and the full neuroendocrine milieu of a living patient are absent. Concentrations, exposure durations, and the two-dimensional context of in vitro growth all shape signaling outcomes, and clinical translation will require validation in animal models and ultimately patient cohorts. Yet the core message is hard to ignore: the beta-2 adrenoceptor is not a simple on switch for cancer, but a context-dependent dial whose setting is determined by the estrogen receptor. As the authors conclude, both estrogen receptor dependent crosstalk and estrogen receptor independent adrenergic mechanisms contribute to the divergent outcomes, a duality that future therapeutic strategies targeting stress signaling in breast cancer will need to navigate with care.

Subject of Research: Estrogen receptor status determines how beta-2 adrenergic signaling regulates proliferation, angiogenic factors, and microRNAs in breast cancer cell lines

Article Title: Selective regulation of β2AR-mediated effects on cellular signaling mechanisms is governed by the estrogen receptor status of the breast cancer cell lines

Article References: Selective regulation of β2AR-mediated effects on cellular signaling mechanisms is governed by the estrogen receptor status of the breast cancer cell lines. (n.d.). https://doi.org/10.1007/s12032-026-03408-1

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03408-1

Keywords: breast cancer, beta-2 adrenoceptor, estrogen receptor, terbutaline, propranolol, ERK, CREB, VEGF-C, nitric oxide, miR-191, miR-21, cell signaling