We conclude that human peritubular cells are a novel model for the investigation of paracrine, including mast cell initiated, interactions in the human testis, which will allow the study of fibrotic processes underlying male idiopathic infertility.

Fibroblast proliferation is a key process in tissue remodeling and mast cells (MCs) are thought to play a crucial role. Having established that the three major MC products, tryptase, histamine and TNF-alpha (TNF) are normally present in human skin MCs, which are in close proximity to dermal fibroblasts, we studied their individual effects on cell cycle-controlled human dermal fibroblasts (HFFF2). These cells express receptors (H1, PAR2, TNFR1/2) for the major MC mediators, but only tryptase or a PAR2 agonist peptide stimulated proliferation and gene expression. TNF was antimitotic, and histamine, while elevating intracellular Ca2+ levels at high concentrations, did not affect proliferation. We conclude that MC products but also composition and numbers of respective receptors on fibroblasts are crucially responsible for fibroproliferative events.

Molecular targets of rapid non-genomic steroid actions are not well known compared to those of the classical transcription pathway, but ion channels have recently been identified to be steroid-sensitive. Especially, in the ovary, the very organ producing high amounts of sex steroids, their rapid actions are not well examined. We now identified a yet unknown target for sex steroids, a voltage-dependent K+ channel (Kv4.2) that contributes to a transient outward K+ current (I(A)) in human granulosa cells (GCs). Sex steroid hormones at concentrations typical for the ovary (1 microM) blocked Kv4.2 thereby attenuating I(A) by about 25% within seconds. We also found both Kv4.2 (KCND2) mRNA and protein in endocrine cells of the human and rhesus macaque ovary, emphasizing the physiological relevance of this channel. Therefore, we propose a role as fast-responding steroid sensor for the Kv4.2 channel. The direct regulation of K+ channel activity by sex steroids might represent a yet unknown mechanism of rapid steroid action in close proximity to the site of steroid production in the primate ovary. Our data might also be important for Kv4 channels in the brain and the cardiovascular system where rapid steroid effects are discussed in the context of prevention of cell death.

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