Thymulin

What it is

Thymulin is a nonapeptide hormone produced exclusively by thymic epithelial cells. Its biological activity depends on zinc binding (forming Zn-FTS/zinc-thymulin); the zinc-free form is biologically inactive. Thymulin induces differentiation of T-cells and enhances functions of various T-cell subsets, acting preferentially on post-thymic precursor cells, cytotoxic T-cells, and suppressor T-cells. Its anti-inflammatory effects are mediated in part by inhibition of NF-κB signaling and suppression of p38 MAPK phosphorylation. Thymulin also suppresses pro-inflammatory cytokines including IL-1α, IL-1β, IL-6, TNF-α, IFN-γ, and IL-17. Thymulin acts as a hypophysiotropic peptide, modulating pituitary function and participating in a bidirectional thymus-neuroendocrine axis. Its production and secretion are regulated by the neuroendocrine system, including prolactin, growth hormone, thyroid hormones, and endogenous opioids. Circulating thymulin declines with age. Extrathymic production of thymulin by non-thymic cells (macrophages, fibroblasts) has been reported under stress conditions; a putative precursor protein (SPATS2L, ~62 kDa) has been identified. The peptide analogue of thymulin (PAT) exerts anti-inflammatory action partially through potentiation of α7-nicotinic acetylcholine receptors.

Class: Thymic peptide hormone (nonapeptide metallopeptide)

What it's studied for

• Anti-inflammatory / immunomodulatory effects in animal models of inflammation Animal studies only
  • Thymulin intraperitoneal administration (various doses and timings over 21 days) significantly reduced thermal hyperalgesia and paw edema in CFA-induced inflammatory rat model; decreased spinal microglial activation, p38 MAPK phosphorylation, and production of TNF-α and IL-6. PMID 30851702 Nasseri et al., International Immunopharmacology (2019)
  • Free and nanoparticle-bound thymulin reduced cytokine production, signaling pathway activity, apoptosis, heat-shock protein and TLR4 expression, and partially restored brain serotonin/melatonin levels in LPS-treated mice with chronic septic inflammation. PMID 29795607 Novoselova et al., PLoS One (2018)
  • Thymulin reduced physiological impairments (blood glucose, body weight, cytokine levels), NF-κB and JNK pathway activity in streptozotocin-induced type 1 diabetes model in mice. PMID 33779346 Novoselova et al., International Journal of Immunopathology and Pharmacology (2021)
• Neuropathic and inflammatory pain (analgesic/anti-hyperalgesic effects) Animal studies only
  • Systemic injections of 1–25 µg thymulin or PAT reduced inflammatory pain and upregulated cytokines induced by endotoxin; PAT exerted analgesic effects equal to or stronger than other anti-inflammatory drugs at lower concentrations. ICV thymulin reduced ET-induced hyperalgesia dose-dependently and inhibited NF-κB activa PMID 17192563 Dardenne, Saade, Safieh-Garabedian, Annals of the New York Academy of Sciences (2006)
  • Review documenting anti-inflammatory and analgesic properties of thymulin and its synthetic analogue PAT in neuropathic pain models, involving modulation of cytokines, microglia, and neuroinflammatory mediators. PMID 30503917 Safieh-Garabedian, Nomikos, Saadé, Neuroscience Letters (2019)
  • PAT reversed inflammatory nociceptive hyperactivity in carrageenan and endotoxin rat models; effects were partially antagonized by α7-nAChR antagonist MLA; PAT potentiated α7-nAChR in electrophysiological recordings. PMID 23880090 Safieh-Garabedian et al., Neuroscience (2013)
• Lung disease / allergic asthma (gene therapy models) Animal studies only
  • A single intratracheal dose of thymulin-expressing plasmids delivered via nanoparticles (after full disease establishment) normalized key pathological features of allergic asthma including chronic inflammation, pulmonary fibrosis, and mechanical dysregulation in mice. PMID 32577505 da Silva et al., Science Advances (2020)
  • DNA nanoparticles carrying thymulin plasmids prevented lung inflammation, collagen deposition, and smooth muscle hypertrophy in an ovalbumin-challenged murine asthma model; thymulin plasmids detected in lungs up to 27 days post-administration. PMID 24556417 da Silva et al., Journal of Controlled Release (2014)
  • Review: thymulin has consistent beneficial effects in experimental models of lung diseases; no toxicity even at high doses; reduces immune response against viral proteins when expressed by adenoviral vectors; inhibits p38 MAPK and NF-κB. PMID 20055713 Santos, Henriques-Coelho, Leite-Moreira, Expert Opinion on Therapeutic Targets (2010)
• Experimental autoimmune encephalomyelitis / multiple sclerosis model Animal studies only
  • Thymulin significantly improved BBB condition, reduced EAE symptoms, decreased IL-6, IL-17, IFN-γ levels and NF-κB activation in splenocytes. Simultaneous administration with Prdx6 resulted in complete symptomatic restoration. PMID 37633587 Lunin et al., Archives of Biochemistry and Biophysics (2023)
  • PBCA nanoparticle-bound thymulin significantly alleviated rEAE symptoms, lowered plasma cytokine levels, decreased NF-κB and SAPK/JNK cascade activation. Nanoparticle-bound thymulin was more effective than free thymulin. PMID 31671728 Lunin et al., International Journal of Molecular Sciences (2019)
• Cancer immunotherapy / age-associated myeloid inflammation Mixed
  • Thymulin suppressed pro-inflammatory cytokine production (IL-1α, IL-1β, IL-6, TNF-α) by aged myeloid cells by inhibiting NF-κB signaling; enhanced antitumor T-cell immunity; improved tumor control and survival; sensitized tumors to anti-PD-L1 therapy in age-dependent manner in mice and identified human relevance throug PMID 42481458 Kanemaru et al., Nature Communications (2026)
• T-cell differentiation and immune function Mixed
  • Thymic hormones including serum thymic factor induce lymphocyte differentiation in vitro and in vivo; act preferentially on post-thymic precursor cells; mode of action involves binding to specific cellular receptors and interaction with adenyl cyclase. PMID 233313 Bach, Journal of Immunopharmacology (1979)
  • Thymulin (nonapeptide) induces differentiation of T-cells and enhances several functions of T-cell subsets in normal or partially thymus-deficient recipients; not toxic; effect on suppressor T-cells noted as most remarkable. PMID 2657247 Bach and Dardenne, Medical Oncology and Tumor Pharmacotherapy (1989)
  • In vitro: thymulin (1–1,000 ng/ml) modulated IL-1α, IL-2, IL-6, and TNF-α release from PBMCs of healthy volunteers and SLE patients; at 1,000 ng/ml significantly inhibited TNF-α in both groups. PMID 8508050 Safieh-Garabedian et al., International Archives of Allergy and Immunology (1993)
• Neuroendocrine regulation (thymus-pituitary-gonadal/somatotropic/corticotropic/thyrotropic axes) Animal studies only
  • Thymulin immunoneutralization reduced circulating gonadotropins at puberty; neonatal thymulin gene therapy in nude mice restored thymulin levels and prevented gonadotropin reduction. PMID 17389714 Goya et al., American Journal of Physiology: Endocrinology and Metabolism (2007)
  • Neonatal thymulin gene therapy in nude mice restored serum thymulin, prevented reduction of brain GnRH neurons and pituitary gonadotropic cells, rescued premature ovarian failure phenotype, and prevented delayed vaginal opening. PMID 22700775 Reggiani et al., Endocrinology (2012)
  • Thymulin immunoneutralization decreased body weight gain, serum GH, and somatotrope cell density; neonatal thymulin gene therapy increased body weight gain, serum thymulin, and somatotrope cell and volume density in nude mice. PMID 22781709 Reggiani et al., Life Sciences (2012)
• Zinc deficiency biomarker / zinc status indicator Human observational
  • Thymulin activity was decreased in three models of mildly zinc-deficient humans (dietary, sickle cell anemia, non-SCA) and corrected by in vivo and in vitro zinc supplementation; proposed as a sensitive indicator of zinc deficiency. PMID 3262625 Prasad et al., Journal of Clinical Investigation (1988)
  • In rats fed low zinc (5 ppm vs 25 ppm), serum thymulin activity was 61% lower, showing greater sensitivity to restricted zinc intake than four other zinc status parameters (serum zinc, extracellular superoxide dismutase, 5'-nucleotidase, liver metallothionein). PMID 32363520 DiSilvestro, Dardenne, Joseph, Biological Trace Element Research (2021)
• HIV / immunodeficiency and opportunistic infection Human observational
  • Active thymulin (ZnFTS) strongly reduced in HIV stage IV with concurrent CD4+ depletion and low zinc. Zinc supplementation (45 mg Zn2+/day for 1 month) combined with AZT therapy restored active thymulin, zincemia, CD4+ cells, and reduced recidivism opportunistic infections by 50%. PMID 10801955 Mocchegiani and Muzzioli, Journal of Nutrition (2000)
• Age-related thymulin decline and thymic endocrine function Human observational
  • Thymulin detectable at birth; gradually increases with age, reaching highest levels in children aged 5–10 years; declines from adolescence, reaching lowest value at 36 years and remaining steady until 80 years (oldest tested) in 93 healthy individuals. PMID 10971509 Consolini et al., Clinical and Experimental Immunology (2000)
  • RIA measured thymulin in human blood: umbilical vessel blood 2191 ± 123 fg/ml; children and adults up to age 20 years 1499 ± 119 fg/ml; adults aged 21–65 years 371 ± 18 fg/ml (highly significant decrease across groups). No thymulin detected in nude or thymectomized animals. PMID 2313103 Safieh et al., Journal of Immunological Methods (1990)
• Gene therapy vector systems for thymulin delivery Animal studies only
  • Single i.m. injection of RAd-metFTS (10^7 PFU/mouse or 10^8 PFU/rat) in thymectomized animals restored serum thymulin levels for at least 110 days (mice) and 130 days (rats) post-injection. PMID 16617301 Reggiani et al., Gene Therapy (2006)
  • Bidirectional regulatable Tet-Off two-adenovector system expressed thymulin and hGFP; expression inhibited by doxycycline (1 mg/ml); ICV injection in rats increased thymulin in CSF; i.m. injection produced progressive increase in serum thymulin inhibitable by DOX in drinking water. PMID 28501652 Zappa-Villar et al., Molecular Immunology (2017)
• Malnutrition and thymic function Human observational
  • Thymulin was severely depleted in thymus glands of Senegalese children with severe protein-energy malnutrition (marasmus, kwashiorkor); thymic Zn content was not depleted and not significantly related to thymulin content. PMID 3136643 Jambon et al., American Journal of Clinical Nutrition (1988)
  • Specific plasma thymulin activity was almost undetectable in infected children; decreased by moderate and severe PEM; normal only in uninfected children in Paris. Concurrent infections were important factors in depressing thymulin. PMID 3124594 Wade et al., American Journal of Clinical Nutrition (1988)
• Glaucoma (primary open angle glaucoma) — plasma thymulin measurement Human observational
  • Highly significant elevation (p<0.001) in plasma thymulin levels in 28 newly diagnosed untreated POAG patients compared with matched controls; authors proposed a possible role for thymulin in POAG pathogenesis. PMID 16217660 Noureddin et al., Graefe's Archive for Clinical and Experimental Ophthalmology (2006)
• Thymulin modulation by GH, prolactin, and thyroid hormones Mixed
  • Children and adults with GH deficiency had markedly reduced active thymulin levels; 6 months of recombinant GH therapy restored thymulin (active and total) to levels comparable to controls. PMID 8957749 Mocchegiani et al., Journal of Endocrinological Investigation (1996)
  • Prolactin (20–100 µg/20g) injected daily in C57BL/6 mice dose-dependently increased thymulin synthesis and secretion; bromocriptine decreased thymulin secretion reversible by coincident PRL; PRL directly stimulated thymulin production in human and murine TEC cultures. PMID 2737149 Dardenne et al., Endocrinology (1989)
  • Persistently low plasma thymulin and serum T3 found in premature infants with various disorders; significant positive correlation between plasma thymulin and serum T3; short-term T3 administration significantly increased plasma thymulin titers in preterm AGA infants. PMID 3597705 Fabris et al., Journal of Clinical Endocrinology and Metabolism (1987)

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.