Neuroendocrine-immune interactions in the neonate

DOMESTIC ANIMAL ENDOCRINOLOGY Vol. 15(5):397– 407, 1998

NEUROENDOCRINE-IMMUNE INTERACTIONS IN THE NEONATE R.L. Matteri,* J.J. Klir,* B.N. Fink,** and R.W. Johnson** *Animal Physiology Research Unit, Agricultural Research Service, United States Department of Agriculture, Columbia, MO 65211 **Dept. of Animal Sciences, University of Illinois, Urbana, IL 61801 Received November 21, 1997 Accepted March 13, 1998

Cytokine responses to lipopolysaccharides in neuroendocrine tissues are age- and tissue-dependent in neonatal pigs. Developmental differences in serum and tissue-specific responses are not necessarily equivalent. Lower levels of cytokine gene expression in neuroendocrine tissues of early neonates potentially could influence neuroendocrine and immune responses to infection. The limited information on neuroendocrine-immune responses and interactions in neonatal farm animals presents significant challenges, as well as opportunities for new discoveries and improvements of livestock production. © Elsevier Science Inc. 1998

INTRODUCTION Central Nervous, Endocrine, and Immune System Interactions. Interactions between nervous, endocrine, and immune systems are clearly involved in critical responses to infectious challenges and the maintenance of health. The ability of operant conditioning to alter immune function can only be explained by communication among physiological systems once thought to function independently (1). The rich complexity of possible interactions is indicated by the presence of receptors for classic neuroendocrine hormones in immune tissues and of receptors for cytokines in neuroendocrine structures. The local production of neuroendocrine hormones in the immune system and of cytokines in neuroendocrine tissues provides a basis for local regulation linking neuroendocrine and immune responses. Very little information exists on the nature and possible importance of neuroendocrine-immune interactions in neonatal farm animals. Neonatal Considerations. Dramatic changes in neuroendocrine function occur during the early neonatal period (2). The ontogeny of the somatotrophic axis is a well-characterized example. Growth hormone (GH) secretion is extremely high in the early postnatal period, a continuation of elevated secretion during late gestation. The ability of the pituitary gland to secrete GH, circulating GH concentrations, and mRNA levels for GH and the GH-releasing hormone (GHRH) receptor decline significantly within the first week after birth (3). Concurrently, increases occur in hepatic GH receptor binding and insulin-like growth factor-1 (IGF-1) secretion (4). The activities of all other major neuroendocrine axes are also developmentally regulated (2). Early developmental changes in immune function also occur (2,5). Although the pig is immunocompetent during late gestation, exposure to many antigens does not begin until birth (6). Maternal antibodies from colostrum provide passive immunity in the early neonatal period. Up to 16 d of age, lymphocytes from blood, spleen, and thymus of young © Elsevier Science Inc. 1998 655 Avenue of the Americas, New York, NY 10010

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Figure 1. Body temperatures in 1-d-old and weaning-age piglets (21–28 d of age). Lipopolysaccharide (LPS; 150 mg/kg) was injected at time 0.

pigs have a minimal ability to proliferate in response to mitogens (7). A dramatic increase in mitogenic response develops between 16 and 28 d of age (7). A well-recognized component of immunological immaturity is the lack of a fever response in neonates (8,9,10). This phenomenon is of considerable interest in both human and veterinary medicine, as the elevated body temperature during fever assists immune function (11). Figure 1 shows changes in body temperatures subsequent to i.p. injection of 150 mg/kg lipopolysaccharide (LPS; serotype 0111:B4; Sigma Chemical Co., St. Louis, MO) in early neonatal and weanling pigs. The younger piglets not only fail to mount a fever response, but lose a significant amount of body temperature. This hypothermia could have significant consequences besides decreased disease resistance, as chilling is a well-known cause of neonatal mortality. Active developmental changes in neuroendocrine and immune function make the piglet an excellent model for studies of neuroendocrine-immune interactions. The following discussion will incorporate recent data obtained in our laboratory using the neonatal pig as a model to study acute-phase responses to LPS. Cytokine Production in Neuroendocrine Tissues. Numerous cytokines, including interleukin-1 (IL-1)b (IL-1b), play important roles in the modulation of neuroendocrineimmune interaction (12). The cytokines IL-6 (IL-6) and tumor necrosis factor (TNF)-alpha (TNF-a) are important components of the acute phase response to infection (13,14). Lymphocytes from umbilical cord blood of newborn infants are deficient in the ability to secrete IL-6 and TNF-a (15,16,17,18). Inadequate cytokine responses to sepsis could contribute to the high levels of morbidity and mortality that occur. Serum IL-6 and TNF-a responses to sepsis in babies, however, do not seem to be compromised (19). The possibility exists, therefore, that local cytokine production in responsive tissues may not reflect serum concentrations, and that early neonatal cytokine production may be relatively deficient in immune and neuroendocrine tissues. Furthermore, extrapolation of the existing data from human or laboratory rodents to farm animals may not be appropriate because of possible differences in the species. We recently addressed these possibilities in an acute-response experiment with 1- and 28-d-old pigs. Piglets were killed 3 hr after LPS injection (150 mg/kg, i.p.) for blood and tissue collection. Serum concentrations of IL-6 and TNF-a, as well as mRNA levels of

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Figure 2. Serum IL-6 and TNF-a concentrations in 1- and 28-d-old piglets. Samples were taken 3 hr after LPS injection. Means bearing different lower case letters differ (p , 0.05, Student-Newman-Keuls multiple comparison). Numbers in parantheses indicate sample size.

these cytokines in pituitary, hypothalamus, spleen, thymus, and liver were evaluated. Serum IL-6 responses did not differ between 1- and 28-d-old piglets (Figure 2). Significant induction of IL-6 gene expression occurred in all tissues (Figure 3). Difference between age groups occurred only in the neuroendocrine tissues. Significant differences in IL-6 gene expression were apparent among tissues. Interestingly, the highest levels of IL-6 mRNA (expressed relative to b-actin mRNA) were found in pituitary tissue, followed in decreasing order by hypothalamus, thymus, liver, and spleen. Similar to IL-6, LPS injection significantly increased circulating TNF-a concentrations (Figure 2). The response, however, was found to be dependent on age with a significantly

Figure 3. IL-6 mRNA levels, relative to b-Actin mRNA, in neuroendocrine and immune tissues of 1- and 28-d-old piglets. Samples were taken 3 hr after LPS injection. The same Y-Axis range is used in all panels.

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Figure 4. TNF-a mRNA levels, relative to b-Actin mRNA, in neuroendocrine and immune tissues of 1- and 28-d-old piglets. Samples were taken 3 hr after LPS injection. The same Y-axis range is used in all panels.

greater elevation in serum TNF-a in the older animals after receiving LPS. Administration of LPS significantly increased TNF-a gene expression in all tissues (Figure 4). Agerelated effects were found in the thymus and pituitary. The 28-d-old pigs had higher thymic TNF-a mRNA levels than the early neonates. A greater induction of pituitary gland TNF-a mRNA was detected in the 28-d-old piglets (Figure 5). The relative abundance of TNF-a mRNA, relative to b-actin mRNA, differed among tissues, but in a pattern different from that of IL-6. Liver contained the greatest amount of TNF-a mRNA, followed in decreasing order by thymus, spleen, pituitary, and hypothalamus. Both IL-6 and TNF-a have been implicated in the regulation of neuroendocrine function during the response to infection. There is evidence for IL-6 regulation of GH

Figure 5. TNF-a MRNA levels, relative to b-Actin mRNA, in neuroendocrine tissues of 1- and 28-d-old piglets. Samples were taken 3 hr after LPS injection. Y-axis range is expanded relative to Figure 4.

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Figure 6. Serum hormone concentrations in 1- and 28-d-old piglets. Samples were taken 3 hr after LPS injection.

(20), PRL (20), LH (21), TSH (20), and ACTH (22) secretion. Likewise, effects of TNF-a have been reported on somatotrophic (23), adrenocortical (24) thyroid (25), lactotrophic (26), and reproductive (27) axes. Neuroendocrine Responses to Immunological Challenge Hypothalamic-Pituitary-Adrenal (HPA) axis. Activation of the neuroendocrine HPA axis during infection is well-documented. Glucocorticoids have been shown to inhibit proinflammatory cytokine production and enhance the release of acute phase proteins (28). Stimulated HPA activity during stress may form an important link between stress and disease (29). Lymphocytes from neonatal pigs with a high, versus a low, cortisol response to stress demonstrate a relatively low proliferative response to mitogenic challenges (30). Disease-activation of the HPA axis during early development can have lasting consequences. Neonatal exposure to endotoxin in rats results in elevated HPA activation attributable to stress, altered hypothalamic corticotropin-releasing hormone (CRH) production, and changes in brain glucocorticoid receptor density in adulthood (31). CRH and pro-opiomelanocortin-derived peptides are produced in immune tissues (32,33). The importance of local production of these compounds relative to neonatal immune function/ development is not known. Modulation of the HPA axis is one of the best-recognized effects of IL-6 on neuroendocrine systems (22). Administration of TNF-a also stimulates the HPA axis (24,34). Whereas cytokine-induced HPA activation involves hypothalamic CRH release, direct pituitary effects have also been demonstrated (22,35). HPA axis activation induced by LPS in young rats, less than 3 wk of age, is lower than that observed in adults (36,37). Because HPA activation precedes elevation in serum IL-1b, IL-6, or TNF-a (38), age-related differences in local cytokine production in neuroendocrine tissues could result in changing levels of HPA activation during early development. Consistent with previous observations in rodents, serum cortisol response to LPS was lowest in the 1-d-old piglets (Figure 6). Hypothalamic IL-6 and pituitary IL-6 and TNF-a responses to

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LPS also were relatively lower in the 1- versus 28-d-old pigs (Figures 3 and 5). Thus, the age-related differences in cytokine production in neuroendocrine tissues could potentially result in differential degrees of HPA activation. It should be noted, however, that cortisol secretion is quite high in both age groups. With the present model, we cannot say whether the difference in cortisol response between ages is of biological significance. Additional experiments using lower levels of LPS and/or different models of immunological challenge are needed. Lactotrophic axis. The immunological activity of prolactin (PRL) is well-documented (39). PRL and its receptor are produced in immune tissues (39). There is evidence for PRL as an important regulatory factor involved in the early development of immune function (40). Some of the actions of PRL include increased CD4/CD8 cell ratios in thymocytes of neonatal mice (41), stimulated NK cell activity (42), and T-cell proliferation and IL-2 release (43). In addition to the pituitary gland and immune tissues, a source of neonatal PRL of developmental importance may be maternal milk (44). PRL receptor mRNA is produced before birth in mouse spleen and thymus (45). In neonatal rats, the expression of the PRL receptor is related to the development of the spleen (40). Experimentallyinduced PRL deficiency in neonatal mice alters development of T and B cells in thymus and spleen (46). Stimulated PRL secretion is thought to be an important component of the acute response to infection (47). The mechanism underlying this stimulation is not well understood; however, TNF-a and IL-6 both increase PRL secretion in cultured rat pituitary cells (48). On the other hand, a hypothalamic site of action for TNF-a on PRL secretion may also exist (26). Elevation of PRL concentrations attributable to psychological stress (49) associated with LPS injection may also be involved. Whereas LPS-induced cytokine gene expression was highest in neuroendocrine tissues of 28- versus 1-d-old piglets (Figures 3 and 5), serum PRL responses were equivalent between age groups (Figure 6). The immunological effectiveness of the similar PRL responses in these piglets may not necessarily be equal, because the response is dependent on the availability of PRL receptors. Splenic PRL receptors increase with age in neonatal rats (40). Developmental changes in PRL receptor abundance in immune tissues of domestic animals remain to be investigated. Somatotrophic axis. A variety of somatotrophic axis hormones (GH, GHRH, somatostatin, IGF-1) have been detected in immune tissues and have been implicated in immunoregulation (50,51). GH is perhaps the best studied pituitary hormone with regard to its importance in immune function (39,52). GH and its receptor are produced in immune tissues of humans (53), rats (54), mice (55), and pigs (Figure 7). The presence of GH during early development is required for the normal development of immune function. Snell dwarf mice lack the Pit-1 transcription factor needed for somatotroph, lactotroph, and thyrotroph development. GH replacement therapy normalizes thymic growth and improves B cell development in Snell dwarf mice (56). Neutralization of GH in neonatal rats results in suppressed development of the thymus and spleen, as well as inhibited antibody production (57). Perturbations in GH secretion attributable to disease, therefore, could alter neonatal effectiveness, and possibly the development of immune function. The effect of immunological challenge on GH secretion may be mediated by cytokines at hypothalamic and/or pituitary levels (12). This response, however, is variable among species. Elevated GH secretion secondary to infection has been observed in humans (58) and sheep (59), whereas a decrease in GH concentrations occurs in rats (60) and cattle (61). In 25-kg pigs, i.v. LPS (20 ug) injection results in a mild, transient elevation in GH secretion between 1 and 2 hr post-injection (62). At 3 hr post-LPS challenge we could find

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Figure 7. Detection of GH (lanes 2– 4, 514 bp) and GH receptor (lanes 5–7, 867 bp) mRNA by RT-PCR. Lane 1, size markers (M); lane 2, pituitary (Pit); lanes 3, 4, 6, and 7, peripheral lymphocytes from 2 representative 28-d-old piglets (p1 and p2); lane 5, liver (Liv).

no significant changes in GH concentrations in 1- or 28-d-old piglets (Figure 6), even though clear cytokine responses were elicited in serum and NE tissues (Figures 2–5). The importance of elevated GH secretion as a component of the acute neuroendocrine-immune response to infection is open to question, given the present data and the variable responses among species. Thyroid axis. Thyroid-stimulating hormone (TSH) is produced in immune tissues in response to mitogens or thyrotropin-releasing hormone (TRH), and has been shown to enhance T cell-dependent and independent antibody production (63). Hormones of the thyroid axis play an important role in early development of immune function. Snell dwarf mice express deficient bone marrow B cell development, which is completely restored by thyroxine treatment (64). In contrast to the consistent stimulatory effects of immunological challenges on HPA and lactotrophic axis activity, thyroid axis activity is decreased. Illness and cytokine treatment reduce TSH and thyroid hormone levels in humans and laboratory rodents (65). Consistent with observations in other species, serum concentrations of TSH are decreased 3 hr following LPS challenge in young pigs (Figure 6). TNF-a rapidly reduces TSH secretion from cultured rat pituitary cells (25). IL-6 also acutely reduces thyroid function, perhaps at the level of the pituitary gland (66). Although cytokine responses in neuroendocrine tissues differed between 1- and 28-d-old pigs (Figures 3 and 5), the suppression of TSH secretion was not affected by age (Figure 6). Interestingly, serum triiodothyronine (T3) concentrations were reduced only in the 28-d-old animals (Figure 6). Perhaps the greater serum TNF-a response in the older animals contributed to the suppression of circulating T3 by directly inhibiting thyroid gland function (67). Although reduced T3 concentrations could eventually develop, reduced availability of T3 does not seem to occur during the acute-phase response in early neonatal pigs. Gonadotrophic axis. We have not yet performed gonadotropin assays on sera from LPS-challenged piglets. Although some cytokines can acutely stimulate gonadotropin release, reproductive hormone secretion is suppressed during chronic illness (12). TNF-a can reduce hypothalamic gonadotropin-releasing hormone (GnRH) release in rats (27). Altered function of the reproductive neuroendocrine axis by infection during early development could have serious consequences. Rats treated with a GnRH antagonist for the first 5 d of life demonstrate severe retardation of thymic development and deficiencies in antibody production as adults in response to antigenic challenges (68).

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Figure 8. Detection of follicle-stimulating hormone receptor (FSH Rec; 354 bp) mRNA by RT-PCR in neonatal porcine thymus gland. 1, positive control (testis); numbers indicate age in days (RNA pooled from 8 animals at each age); 2, negative control; M, DNA size markers.

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