衰老细胞产生衰老相关分泌表型（SASP），其中涉及具有多种且有时相互矛盾的活性的因子。一种关键的 SASP 因子白细胞介素 6 (IL-6) 具有通过自分泌作用放大 SASP 产生细胞的细胞衰老的潜力，同时诱导邻近细胞的增殖。对比作用的潜在机制仍不清楚。我们发现衰老作用不涉及IL-6的分泌，也不涉及与膜中表达的受体的相互作用，而是通过内分泌机制放大。 IL-6 与位于顺行交通特殊结构中的细胞内 IL-6 受体相互作用，通过胞质 DNA、cGAS-STING 和 NFκB 激活来维持分泌内衰老。这条由细胞内 IL-6 触发的途径显着促进细胞自主诱导衰老并影响肿瘤生长控制。在 NOD/SCID 小鼠中，生长激素衰老细胞中 IL-6 的失活会将其转化为强致瘤细胞，而 IL-6 的重新表达可恢复肿瘤生长的衰老控制。分泌内衰老 IL-6 途径在三种治疗诱导衰老的人类细胞模型中得到进一步证实。与旁分泌致瘤作用相比，细胞内信号传导的区室化为 IL-6 提供了一条维持细胞自主衰老细胞、驱动 SASP 的途径，并为临床考虑基于衰老的疗法开辟了新途径。© 2024作者。衰老细胞由解剖学会和约翰·威利出版

Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.