Tumor Necrosis Factor-alpha

Rheumatoid arthritis (RA) is a systemic autoimmune disease that, beyond joint destruction, contributes to neuropsychiatric symptoms such as depression, anxiety, and cognitive impairment. These symptoms are often underrecognized despite their major impact on quality of life. Accumulating evidence suggests that pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), play a key role in this neuroimmune interface. This narrative review examined 16 clinical studies evaluating the effects of biologic therapies targeting TNF-α and IL-6 on mental health outcomes in RA. The total study population comprised 9939 patients, including 2467 treated with TNF-α inhibitors and 7472 with IL-6 or IL-6 receptor inhibitors. TNF-α inhibitors were associated with improved depressive symptoms and emotional well-being. IL-6 inhibitors demonstrated similar psychiatric benefits, particularly in patients with elevated IL-6 levels. The findings highlight that biological therapies in RA may influence not only physical symptoms but also mental health, likely through modulation of neuroimmune pathways including blood-brain barrier permeability, microglial activation, and HPA axis regulation. Future research is needed to clarify these effects in populations stratified by psychiatric comorbidity and inflammatory biomarkers. Clinical implications: Incorporating psychiatric symptom screening and considering neuroinflammatory profiles may help guide the selection of biologic therapy in RA, particularly in patients with comorbid depression or fatigue.

NK cell-based immunotherapy of solid tumors has been shown to be increasingly successful, but much effort is still needed to optimize its efficacy. This study explores the effects of treatment with low, non-toxic doses of IFN-γ and TNF-α on the susceptibility of breast cancer (BC) cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) cultured in 2D and 3D as spheroids, to NK cell-mediated antitumor function. We evaluated the expression of (i) ligands for NK cell-activating receptors on BC cells, (ii) death and adhesion molecules on BC cells, and (iii) the expression of NK cell-receptors on NK cells infiltrating BC spheroids. Cytokine treatment significantly increased the expression of FAS, TRAIL-R2, and ICAM-1 in all BC cell lines, enhancing NK cell-mediated apoptosis and promoting NK cell-tumor cell conjugate formation. Differently, the expression of ligands for activating receptors remained essentially unchanged. In BC spheroids, the treatment with IFN-γ and TNF-α enhanced NK-cell infiltration, with increased expression of activating receptors (NKG2D, DNAM-1, NKp30, and NKp46) on infiltrating NK cells. However, regardless of treatment, markers of NK cell exhaustion, such as PD-1 and CTLA-4, were also upregulated, the latter especially in triple-negative BC (TNBC) MDA-MB-231 spheroids, thus suggesting an exhausted phenotype of NK cells infiltrating spheroids despite activation. Cytokine treatment resulted in a significant NK cell-mediated reduction in spheroid size, accompanied by an increased apoptotic state, with effects more pronounced in MCF-7 than in MDA-MB-231 spheroids. These results indicate that, although the treatment with IFN-γ and TNF-α improves NK cell-mediated tumor interaction and apoptosis, its therapeutic efficacy may be dependent on the BC subtype, with TNBC spheroids showing greater resistance. These findings highlight the importance of the tumor microenvironment (TME) in shaping NK cell responses and suggest that combining IFN-γ and TNF-α treatments with NK-cell-based immunotherapeutic strategies may improve treatment outcomes, particularly for more aggressive BC subtypes.

The probiotic Escherichia coli Nissle 1917 (EcN), clinically used for ulcerative colitis (UC) due to its safety and genetic tractability, exhibits limited therapeutic efficacy owing to poor targeting and colonization at inflamed sites. Phosphatidylserine (PS) exposure increases on apoptotic colon epithelial cells during UC progression, suggesting PS-targeting could enhance EcN localization. Here, EcN is engineered to surface-display Annexin A5 (ANXA5), a PS-binding protein, to improve inflammation targeting and colonization. Since TNF-α drives UC pathogenesis and anti-TNF-α biologics face cost and safety limitations, the secretion-hindering lpp gene is concurrently knocked out in ANXA5-expressing EcN, creating the inflammation-targeted, secretion-enhanced EcNΔlpp::A5. This base strain is further modified to secrete an anti-TNF-α nanobody (aTN), generating EcNΔlpp::A5-aTN. Both engineered strains demonstrate significantly stronger colonic colonization versus wild-type EcN, effectively attenuating oxidative stress-mediated epithelial apoptosis, restoring mucosal barriers, improving immune-microbiota balance, and alleviating murine colitis. EcNΔlpp::A5-aTN shows superior efficacy to EcNΔlpp::A5. This study develops an engineered EcN system with enhanced targeting, colonization, and secretion. By efficiently delivering anti-TNF-α nanobodies, EcNΔlpp::A5-aTN exhibits strong therapeutic potential for UC, overcoming limitations that hinder the clinical application of wild-type EcN.

BackgroundThe cytokine tumor necrosis factor-alpha (TNF-α) regulates inflammatory responses in infectious and neurodegenerative diseases and also affects neuronal function. The role of TNF-α in the activation of microglial cells (resident central nervous system macrophages), including the impact on neuronal survival, excitability, and synaptic transmission is incompletely defined, however. We explored the effects of chronic TNF-α exposure (72 h) on microglia and neurons in organotypic hippocampal slice cultures from male and female rats, i.e., postnatal cortex tissue lacking leukocyte invasion and adaptive immunity.MethodsWe applied gene expression analysis, biochemical assays, immunohistochemistry, electrophysiology by extracellular (local field potential) and intracellular (intrinsic membrane properties) recordings, and pharmacological ablation of the microglial cell population. We mainly focused on carbachol-induced neural network oscillations (brain waves) in the gamma frequency band (30-70 Hz) that underlie higher cognitive functions such as perception, attention, and memory.ResultsTNF-α induced microglial proliferation and upregulation of genes related to inflammation and oxidative stress such as Il6 (interleukin-6), Nos2 [inducible nitric oxide (NO) synthase, iNOS] and Sod2 (superoxide dismutase 2), which was accompanied by a decreased number of slices showing gamma oscillations in extracellular recordings. Notably, a fraction of slices presented neural bursting reflecting hyperexcitability in the tissue. Neuronal dysfunction was absent during acute TNF-α exposure (30 min). When paired with the lymphocyte cytokine interferon-gamma (IFN-γ), TNF-α induced an amplified neuroinflammation response dominated by bursting or loss of electrical activity. In intracellular recordings, neurons showed a brief burst of action potentials followed by slowing of spiking with pronounced afterhyperpolarization (switch from regular to burst firing behavior) during depolarizing current injection. Notably, the impairments could be attenuated by inhibition of iNOS and NADPH oxidase, glucose supplementation, microglial depletion or blockade of TNF receptor 1 (TNFR1) signaling with small molecule drugs, RIPA-56 and ICCB-19.ConclusionsOur data provide mechanistic insight into TNF-α- and IFN-γ-induced neuronal impairments mediated by microglial NO, metabolic and oxidative stress, and demonstrate functional neuroprotection by pharmacology. Our study extends the pathophysiological understanding of diseases such as sepsis, multiple sclerosis, Alzheimer's disease, depression and schizophrenia featuring activated microglia, infiltrating monocytes and T cells, and/or blood-brain barrier leakage.