No abstract

Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

No abstract

Observations of apo-metallothionein (apo-MT) have been made under a variety of physiologic circumstances, including zinc deficiency in cell culture and in rodents, cellular induction of MT by dexamethasone with concurrent Zn deficiency, a variety of tumors under normal Zn conditions, MT induction by Zn and Bi citrate, induction of hepatic MT after tumor cell injection into nude mice, and overexpression of cardiac MT in MT transgenic mice. Experiments demonstrating both the lability of Zn and Cu bound to MT and the cellular stability of apo-MT are described to help rationalize the widespread presence of this metal-depleted species. Finally, comparative in vitro and cellular experiments examined the relative reactivity of Zn- and apo-MT with nitric oxide species, showing that apo-MT is much more reactive chemically and that in cells it may be a principal reactive species within the MT pool.