A long-acting anti-IL-8 antibody improves inflammation and fibrosis in endometriosis.

Current pharmacological treatments for endometriosis are limited to hormonal agents that can relieve pain but cannot cure the disease. Therefore, the development of a disease-modifying drug for endometriosis is an unmet medical need. By studying human endometriotic samples, we found that the progression of endometriosis was associated with the development of inflammation and fibrosis. In addition, IL-8 expression was highly up-regulated in endometriotic tissues and closely correlated with disease progression. We created a long-acting recycling antibody against IL-8 (AMY109) and evaluated its clinical potency. Because rodents do not produce IL-8 and do not experience menstruation, we analyzed the lesions in cynomolgus monkeys that spontaneously developed endometriosis and in a surgically induced endometriosis monkey model. Both spontaneously developed and surgically induced endometriotic lesions demonstrated pathophysiology that was highly similar to that of human endometriosis. Once-a-month subcutaneous injection of AMY109 to monkeys with surgically induced endometriosis reduced the volume of nodular lesions, lowered the Revised American Society for Reproductive Medicine score as modified for monkeys, and ameliorated fibrosis and adhesions. In addition, experiments using cells derived from human endometriosis revealed that AMY109 inhibited the recruitment of neutrophils to endometriotic lesions and the production of monocyte chemoattractant protein-1 from neutrophils. Thus, AMY109 may represent a disease-modifying therapy for patients with endometriosis.

Molecular elements of the regulatory control of keratin filament modulator AHF/trichohyalin in the hair follicle.

Hairs in mammals undergo well-programmed cyclic development, which is strictly controlled by the surrounding hair follicle cells. Among hair follicle epithelia the inner root sheath (IRS) directly envelops the hair shaft to mechanically support its cyclic growth, but the molecular mechanism underlying its sharp regulation remains obscure. Here, we identify regulatory elements for the expression of the IRS-specific protein AHF (Anagenic Hair Follicle antigen), the putative mouse orthologue of trichohyalin (THH), which plays a key role in the assembly of keratin intermediate filaments (IFs) during the hair cycle. AHF becomes abundantly present in the growing anagenic hair follicle and is suddenly diminished as the tissue enters into the subsequent resting stages under the control of ubiquitin-dependent proteolysis. Using primary human keratinocytes, we found that bone morphogenic protein-4 facilitates THH transcription, and intriguingly, a nuclear lamina component plays a key role in the posttranslational stabilization of THH protein. Silencing of the lamin A/C gene leads to rapi THH degradation, whereas exogenously introduced lamin C, but not lamin A, protects THH from proteolytic elimination. These results shed light on the strict molecular mechanisms which control stage- and compartment-specific IF assemblies in support of the cyclic development of the hair shaft.

Identification of a cis-acting element required for dendritic targeting of activity-regulated cytoskeleton-associated protein mRNA.

The mRNA encoding activity-regulated cytoskeleton-associated protein (Arc) is known to be targeted to dendritic regions that have received strong synaptic inputs. However, the cis-acting elements in Arc mRNA that mediate dendritic targeting have not been identified. To identify the dendritic targeting element (DTE) in rat Arc mRNA, we expressed reporter mRNAs containing various regions of Arc in primary hippocampal neurones and analysed their subcellular distribution by in situ hybridization. Here, we report that the 3'-untranslated region of rat Arc mRNA contains a 350-nucleotide DTE with strong dendritic targeting activity and another 370-nucleotide sequence with weaker dendritic targeting activity. The 350-nucleotide DTE does not share any obvious sequence similarity with other known DTEs previously reported.