Neuroendocrine Hormone Release by Cells of the Immune System

There is now substantial evidence that cells of the immune system produce neuroendocrine hormones. This was first established for ACTH and subsequently for TSH, GH, PRL, LH, FSH and the hypothalamic hormones SOM, CRH, GHRH, and LHRH (Weigent and Blalock 1995). The evidence supports the idea that neuroendocrine peptides and neurotransmitters, endogenous to the immune system, are used for both intraimmune system regulation, as well as for bidirectional communication between the immune and neuroendocrine systems. Although the structures of these immune-cell-derived peptides are, for the most part, identical to those identified in the neuroendocrine system, both similarities and differences exist in the mechanism of synthesis to the patterns previously described in the neuroendocrine system.

At least two possibilities exist concerning the potential function of these peptide hormones produced by the immune system. First they act on their classic neuroendocrine target tissues. Second, they may serve as endogenous regulators of the immune system. A number of investigators have now been able to demonstrate that such regulation is endogenous to the immune system. Specifically, TSH is a pituitary hormone that can be produced by lymphocytes in response to TRH and, like TSH, TRH enhanced the in vitro antibody response (Kruger et al. 1989). This was the first demonstration that a neuroendocrine hormone (TSH) can function as an endogenous regulator within the immune system. A large number of human hematopoietic cell lines and tumors synthesize and release PRL (Montgomery 2001). The synthesis and secretion of 23 kDa PRL from cells of the immune system is well established, although size heterogeneity is evident (11 to 60 kDa) (Kooijman and Gerlo 2002). Most forms appear to exhibit some biological activity in proliferative assays (Montgomery, Shen, Ulrich, Steiner, Parrish, and Zukoski 1992). The evidence suggests a low constitutive level of PRL expression inducible by IL-2 and inhibited by dexamethasone. In T cells, PRL is translocated to the nucleus in an IL-2-dependent P-13 kinase pathway inhibited by rapamycin (Clevenger et al. 1990). Immune-cell-derived PRL most likely plays a role in hematopietic cell differentiation and proliferation. In another study, antibody to PRL was shown to inhibit mitogenesis through neutralization of the lymphocyte-associated PRL (Clevenger et al. 1992). Furthermore, coordinate gene expression of LHRH and the LHRH receptor has been shown in the Nb2 T-cell line after PRL stimulation (Wilson, Yu-Lee, and Kelley 1995).

Two approaches have been utilized to obtain convincing evidence that endogenous neuroendocrine peptides have autocrine or paracrine immunoregulatory functions. First, an opiate antagonist was shown to indirectly block CRH enhancement of NK cell activity by inhibiting the action of immunocyte-derived opioid peptides (Carr, DeCosta, Jacobson, Rice, and Blalock 1990). Second, we have used an antisense oligodeoxynucleotide (ODN) to specifically inhibit leukocyte production of GH which resulted in reduced basal rates of DNA synthesis (Weigent, Blalock, and LeBoeuf 1991). Another group examining SOM found that antisense oligodeoxynucleotides to SOM dramatically increased lymphocyte proliferation in culture (Aguila, Rodriguez, Aguila-Mansila, and Lee 1996). Additionally, LHRH

agonists were found to diminish NK cell activity, stimulate T-cell proliferation, and increase IL-2-receptor expression suggesting an important role for LHRH in the regulation of the immune response (Batticane, Morale, Galio, Farinella, and Marchetti 1991).

Another major function of GH produced by cells of the immune system is the induction of the synthesis of IGF-1, which, in turn, may inhibit the synthesis of both lymphocyte GH mRNA and protein. The results in T cell lines supported a role for locally generated IGF-1 in the mediation of GH action on T-lymphocytes and indicated the effect was mediated via the type 1 IGF receptor (Geffner, Bersch, Lippe, Rosenfeld, Hintz, and Golde 1990). We could detect IGF-1 in primary rat spleen cells by direct immunofluorescence with specific IGF-1 antibodies, immunoaffinity purification, HPLC, and a fibroblast proliferation bioassay. The data showed that IGF-1 was de novo synthesized and similar to serum IGF-1 in molecular weight, antigenicity, and bioactivity (Baxter, Blalock, and Weigent 1991). The major work examining the expression of the IGF-1 mRNA in the mouse lymphohemopoietic system has been done by Kelley and colleagues in macrophages (Arkins, Rebeiz, Biragyn, Reese, and Kelley 1993). Their results establish that murine macrophages express abundant insulin-like growth factor-1 class 1 Ea and Eb transcripts. Further, their data suggest myeloid rather than lymphoid cells are the major source of IGF-1 that is associated with differentiation of bone marrow macrophages (Arkins et al. 1993). Thus, in macrophages, initiation of transcription is primarily within exon 1 that is typical of extrahepatic tissues with a higher percentage of Eb transcripts that is typical of hepatic tissues. The significance of different leader peptides and E terminal domains on IGF-1 is unknown but may influence targeting, processing or stability. Kelley and coworkers have also shown that mature adherent myeloid cells synthesize and secrete a substantial amount of IGF-binding proteins (BPs), whereas less differentiated or nonadherent myeloid cells produce fewer IGF-BPs. Premyeloid cells, mature T cells, and primary murine thymocytes did not synthesize detectable IGF-BPs (Li et al. 1996). Additional gel-shift, Northern blotting, and sequencing analysis showed that the IGF-BP secreted by mature adherent macrophages was IGF-BP4. Taken together, the presence of IGF-1, the IGF-1 receptor and IGF-BPs, particularly in myeloid cells, strongly supports the suggestion that the IGF system is important in hematopoiesis and inflammation. The findings support the existence of a complete regulatory loop within cells of the immune system, and they provide a molecular basis whereby GHRH, GH, IGF-1 and their binding proteins may be intimately involved in regulating each other's synthesis (Weigent, Baxter, and Blalock 1992). Our most recent findings in a T cell-line show that endogenous GH promotes nitric oxide production, up-regulation of IGF-1 receptors and Bcl2 protein along with an inhibition of superoxide formation, clearly establishing a role for lymphocyte GH in apoptosis (Arnold and Weigent 2003).

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