Thyroid Hormones Modulate Thyrotropin-Releasing Hormone Biosynthesis in Tissues Outside the Hypothalamic-Pituitary Axis of Male Rats*

Abstract

In the present study we have examined the in vivo effects of thyroid hormone and TRH on secretory tissue concentrations of TRH and TRH-Gly (pGlu-His-Pro-Gly), a TRH precursor. Within secretory granules, TRH-Gly is converted to TRH through alpha-amidation of the C-terminal proline residue, using Gly as the NH2 donor. Using specific RIA, we measured the TRH-Gly immunoreactivity (TRH-Gly-IR) and TRH-IR concentrations in tissues from the reproductive and gastrointestinal systems, adrenals, and other internal organs in euthyroid, hypothyroid, and T4-treated 250-g Sprague-Dawley male rats. TRH-Gly-IR concentrations were more than 2-fold higher than TRH-IR concentrations within the adrenal, pancreas, bowel, and stomach at the time of death. Untreated hypothyroidism and exogenous TRH significantly increased adrenal TRH-Gly-IR levels. Pancreatic TRH-Gly levels increased about 2-fold in hypothyroid rats. Incubation at 60 C significantly increased TRH-Gly-IR levels in the pancreas, adrenal, bowel, stomach, and epididymis by 14-, 3-, 6-, 6-, and 6-fold, respectively. Also after 60 C incubation increases in the TRH-Gly-IR/TRH-IR ratio of 2.7-, 4-, and 1.7-fold were observed in the pancreas, epididymis, and bowel, respectively. Pooled tissue extracts were fractionated by cation exchange and reverse phase HPLC for characterization of TRH-Gly-IR. Both chromatographic methods revealed a major peak of TRH-Gly-IR coeluting with synthetic TRH-Gly. Incubation at 60 C caused 13.5-, 4.1-, 1.5-, and 5-fold increments in the TRH-Gly-IR for adrenal, pancreas, prostate, and thyroid, respectively, compared to the immediately extracted control aliquots. Cation exchange and reverse phase HPLC also revealed production of higher mol wt TRH precursor peptides after incubation at 60 C for 4 or 20 h. Only the TRH-Gly-IR peak coeluting with pGlu-His-Pro-Gly was converted into TRH by rat brain alpha-amidating enzyme. The data suggest that biosynthesis of TRH occurs in rat extrahypothalamic tissues and may be modulated by thyroid status, iv TRH, and selective thermal inactivation of enzymes that convert prepro-TRH to TRH.

High Levels of Thyrotropin-Releasing Hormone Precursor Peptide Immunoreactivity and Binding Substance Occur in Human Cerebrospinal Fluid

“…The 100-and 300-fold greater levels of TRH-Gly-IR com pared to the TRH-IR levels in human CSF is similar to the cor responding ratio in extrahypothalamic tissue extracts [8,9] but this ratio is essentially reversed in extracts of brain tissue [17,22]. Possible explanations for the unexpectedly high values of TRH-Gly-IR in CSF include (I) extra-CNS tissues secrete TRH-containing vesicles with a high proportion of TRH-Gly-IR into the CSF, and (2) the TRH-Gly-binding substance of CSF protects TRH-Gly from enzymatic degradation while TRH re mains unprotected and subject to rapid destruction.…”

“…Alpha-amidation of pGlu-His-ProGly (TRH-Gly) is the final, and in most tissues, rate-limiting step in TRH biosynthesis [8,9]. Experiments using an antibody directed against TRH-Gly indicated that, in some tissues, the levels of this TRH precursor can be more than 100-fold higher than those for TRH [8].…”

The Thyrotropin (Thyroid-Stimulating Hormone) Receptor Is Expressed on Murine Dendritic Cells and on a Subset of CD45RBhigh Lymph Node T Cells: Functional Role for Thyroid-Stimulating Hormone During Immune Activation

“…Still to be understood in this scenario is the precise cell population(s) involved in TRH production, and the nature of the inductive signal for TRH-Gly conversion to TRH; i.e., whether it is mediated by external Ag-driven stimuli or whether signals from the host "feed in" during the early phase of the immune-endocrine process. Some evidence for an internal signal currently exists from experiments which demonstrate increased TRH-Gly levels following thyroid hormone (T 3 or T 4 ) stimulation (57). Additional studies aimed at delineating the participation of TRH and other peptide mediators can be done using the hormoneresponsive cells described here to understand the functional involvement of immune-endocrine interactions on the immune response.…”

Thyrotropin-releasing Hormone Immunoreactivity in Rat Adrenal Tissue Is Localized in Mast Cells

“…Several studies have indicated the presence of TRH in rat adrenal gland (Simard et al 1989;Fuse et al 1990), but its cellular localization and physiological significance were unknown. The present study demonstrates that adrenal TRH derives from a precursor molecule similar or closely related to hypothalamic pro-TRH.…”

“…Although TRH in pharmacological concentrations has been demonstrated to exert multiple effects on tissues other than the pituitary, the physiological significance of the peripheral TRH and the respective contribution of each tissue from which it comes have not been clearly established. In that regard, TRH has been identified in extracts of rat adrenal glands (Simard et al 1989;Fuse et al 1990), but the cellular localization of TRH immunoreactivity and whether adrenal and neural pro-TRHs are identical remain unknown. In the present study we investigated the presence of both TRH and a prepro-TRH connecting peptide, the prepro-TRH[160-169] (Ps4), in rat adrenal glands by combining molecular sieve filtration and HPLC with EIA detection.…”