Proopiomelanocortin (POMC) is a precursor protein for many peptide hormones such as adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormones (MSH) and beta-endorphin (beta-END). The major tissue that synthesizes POMC-derived peptides is the pituitary gland, where POMC is proteolytically processed by prohormone convertases (PC) 1 and 2 and by carboxypeptidase E (CPE) to cleave POMC to biologically active ACTH and beta-END. Non-pituitary tissues such as immune cells can also produce beta;-END. Those cells migrate into inflamed tissue where they release opioid peptides and attenuate inflammatory pain by activating opioid receptors on peripheral terminals of sensory neurons. Overall knowledge about the regulation and production of POMC in immune cells is scarce, especially with respect to cells of the adaptive immune system (lymphocytes). Under naïve/unstimulated conditions, Pomc mRNA expression may be repressed in immune cells. The major questions of the present study were whether and how Pomc is repressed in lymphocytes under naïve conditions, which cell subsets can be stimulated to express Pomc and whether the post-translational processing involves the same proteolytic enzymes as in the pituitary. To study the regulatory mechanisms of POMC expression and beta-END formation in lymphocytes and their subsets (B and T cells), we used isolated cells from lymph node (LN) tissue of rats with/without hind paw inflammation induced by intraplantar injection of complete Freund s adjuvant (CFA).In conclusion, the present studies suggest that the expression of Pomc and beta-END production in rat lymphocytes involve additional mechanisms to DNA-methylation, that are overcome under certain circumstances as in acute CFA-induced inflammation and IL-4 stimulation of mixed cell cultures. Although the key factor triggering Pomc mRNA expression in B cells remains unknown, the event seems to be cytokine- and JAK/STAT-dependent. The processing of POMC into beta-END seems to be linked to PC1. These findings may help to develop strategies for pain therapy by boosting opioid peptide production in immune cells. This might be especially interesting for chronic inflammation.
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