Extrathymic production of thymulin induced by oxidative stress, heat shock, apoptosis, or necrosis

Abstract

Thymic peptides are immune regulators produced mainly in the thymus. However, thymic peptides such as thymosin-α and thymopoietin have precursors widely expressed outside the thymus, localized in cell nuclei, and involved in vital nuclear functions. In stress-related conditions, they can relocalize. We hypothesized that another thymic peptide, thymulin, could be similarly produced by non-thymic cells during stress and have a precursor therein. Non-thymic cells, including macrophages and fibroblasts, were exposed to oxidative stress, heat, apoptosis, or necrosis. Extracellular thymulin was identified in media of both cell types 2 h after exposure to stress or lethal signals. Therefore, thymulin is released by non-thymic cells. To examine possible thymulin precursors in non-thymic cells, macrophage lysates were analyzed by western blotting. Bands stained with anti-thymulin antibody were detected in two locations, approximately 60 kDa and 10 kDa, which may be a possible precursor and intermediate. All of the exposures except for heat were effective for induction of the 10 kDa protein. BLAST search using thymulin sequence identified SPATS2L, an intranucleolar stress-response protein with molecular weight of 62 kDa, containing thymulin-like sequence. Comparisons of blots stained with anti-thymulin and anti-SPATS2L antibodies indicate that SPATS2L may be a possible candidate for the precursor of thymulin.

Exosomes, DAMPs and miRNA: Features of Stress Physiology and Immune Homeostasis

“…Danger/Damage Associated Molecular Patterns (DAMPs) are endogenous molecules derived from self, increased after cellular or oxidative stress [28], tissue damage [29], and stressor exposure [10, 30] and stimulate innate immunity and sterile inflammation. In most instances these self-molecules only function as DAMPs when they are in the extracellular environment due to stress-evoked release and/or necrotic cell death.…”

Thymulin and peroxiredoxin 6 have protective effects against streptozotocin-induced type 1 diabetes in mice

“…24 Furthermore, our recent study showed a role of thymulin in developing a fast response against oxidative stress in a damage-associated molecular pattern (DAMP)-like manner, restraining the inflammatory reaction. 25 Administration of STZ causes a sharp increase in the expression of JNK, which is considered a crucial factor in the STZ-induced β-cells death. 26 The JNK pathway is also involved in pathogenesis of diabetes.…”

“… 24 Furthermore, our recent study showed a role of thymulin in developing a fast response against oxidative stress in a damage-associated molecular pattern (DAMP)-like manner, restraining the inflammatory reaction. 25 …”

In mice transgenic for IGF1 under keratin-14 promoter, lifespan is decreased and the rates of aging and thymus involution are accelerated

“…Ironically, virtually nothing is known still about the molecular targets of one of the main secretory products of the thymus, i.e. thymulin, and about the mechanisms of its production [39], although almost half a century has passed since thymulin had been discovered. However, numerous interrelationships between thymus secretory products, including thymulin, and the components of the immunoneuroendocrine system are known [27].…”