Tumor Necrosis Factor/Cachectin and Interleukin-1 Secretion by Cord Blood Monocytes from Premature and Term Neonates

Abstract

ABSTRACT. Blood monocytes produce two well-defined cytokines, tumor necrosis factor/cachectin (TNF) and 11-1, that have multiple immunologic and inflammatory functions. This study examined the secretion of these cytokines by cord blood monocytes from preterm and term neonates stimulated with or without lipopolysaccharide (LPS). Seventeen samples (eight preterm, nine term) were collected. Supernatants of monocytes were assayed for activities of IL-1 (mitogenesis for mouse thymocytes) and TNF (cytotoxicity for L929 cells). IL-1 and TNF activities were not significant in supernatants of unstimulated monocytes from either preterm or term infants. IL-1 secretion by LPSstimulated monocytes from term and preterm neonates was comparable to IL-1 activity by monocytes from adults, but TNF activity by LPS-stimulated monocytes from preterm neonates was significantly less than that from monocytes of either term or adult groups (p < 0.05). TNF activity in supernatants of LPS-stimulated monocytes was neutralized 100% by monoclonal antibody to TNF-a; IL-1 activity was neutralized 80% by polyclonal antiserum to IL-1-P. Given the multifactorial biologic activities of TNF, the decreased secretion of TNF by monocytes from preterm neonates may be significant in describing mechanisms for the increased susceptibility of the preterm neonate to infection. (Pediatr Res 25342-346, 1989) (6,(8)(9)(10) (13,14 Abbreviations TNF, tumor necrosis factor LPS, lipopolysaccharide The immunologic competence o f the neonate has been an area o f concern both for the clinician and the researcher because neonates have an increased risk for sepsis and often do not manifest the typical signs, such as fever, that are seen in older children ( I ) . Most studies o f the immune and inflammatory response from neonates have examined the functions o f lymphocytes and neutrophils. For example, lymphocytes from neonates respond adequately to mitogens and antigens (2-4), but lymphokine production is variable (2, 5). Polymorphonuclear cells o f . Blood monocytes are derived from a granulocyte-macrophage progenitor cell ( 1 1 ) and probably first appear in the circulation during the 20th-22nd wk o f gestation (10). Effector functions o f monocytes obtained from neonates such as phagocytosis and bactericidal activity are comparable to those o f monocytes from adults but chemotaxis is decreased ( 10). IL-1 and TNF, also known as cachectin, are two well-defined cytokines produced by mononuclear phagocytes responsible for induction o f fever and possibly cachexia (8, 12). IL-1 and TNF are distinct proteins with mol wt o f 17 kD (8). Both are produced by blood monocytes and tissue macrophages when stimulated with bacterial LPS. The production o f these cytokines, however, alters as blood monocytes differentiate into tissue macrophages

TNF-α-induced apoptosis in neonatal lymphocytes: TNFRp55 expression and downstream pathways of apoptosis

“…In summary, cord blood lymphocytes not only produce a lesser amount of TNF (English et al, 39 Weatherstone and Rich, 40 present study), but they are also less susceptible to TNF-␣-induced apoptosis. The decreased susceptibility to TNF-␣-induced apoptosis in cord blood lymphocytes is associated with decreased expression of TNFR-I and certain adapter molecules, and with decreased expression and activity of both initiator and effector caspases.…”

“…However, cord blood mononuclear cells have been shown to produce lower amounts of TNF-␣ as compared to peripheral blood mononuclear cells. 39,40 The role of activation of NF-B in decreased TNF-␣-induced apoptosis in cord blood T cells remains to be examined.…”

“…In addition, neonatal mononuclear cells produce significantly less TNF-␣ than peripheral blood mononuclear cells. 39,40 Therefore, in this study we compared TNF-␣-induced apoptosis between cord blood and peripheral blood lymphocytes. Our data show that decreased TNF-␣-induced apoptosis in cord blood T cell subsets is associated with decreased expression of TNFR-I, TRADD, and caspase 3, and decreased activity of both caspase 8 and caspase 3.…”

Intracellular cytokine profile of cord and adult blood monocytes

“…A reduced mRNA expression and protein production of TNF-␣ in antigen-or mitogen-stimulated cord vs adult blood monocytes and MNCs were described by others and we confirmed that PPD also had a low effect on CB monocytes, whereas stimulated AB monocytes produced significant TNF-␣ levels in culture supernatant. 9,[18][19][20] CB lymphocytes are known to be naive cells compared to AB lymphocytes as revealed by CD45RA + expression. 15,21,22 In our study, analysis of the monocyte populations showed that both CB and AB monocytes contained a low proportion of CD45RA + cells, but AB mono- cytes also presented a memory profile as determined by the specific marker CD45RO (Table 1).…”

“…[15][16][17][18][19] Peripheral blood monocytes belonged to the mononuclear phagocytic system which plays a crucial role in phagocytosis and in accessory and immunoregulatory functions. These cells are known to produce a variety of soluble mediators like IL-1␤ and TNF-␣.…”