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Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward Th2-type lymphocyte pattern in severely injured male trauma patients

Spolarics, Zoltán MD, PhD; Siddiqi, Muhammad MD; Siegel, John H. MD; Garcia, Zenaida C. BS; Stein, Dana S. BS; Denny, Thomas MSc; Deitch, Edwin A. MD

doi: 10.1097/01.CCM.0000063579.43470.AA

Objective To determine the effect of major trauma on the cytokine-producing activity of monocytes and CD4+ T cells in a homogeneous cohort of patients as well as to determine the relationship between monocyte and T-lymphocyte responses and clinical outcome.

Settings Surgical intensive care units of a trauma center and flow cytometry and experimental laboratories at a teaching hospital.

Design Prospective cohort clinical study with measurements of white cell cytokine-producing activity on days 2, 5, and 10 postinjury. The number of cytokine-producing CD14+ monocytes, CD4+, and CD8+ T cells were determined in whole blood using flow cytometry combined with the intracellular cytokine staining method. Basal and lipopolysaccharide-stimulated interleukin (IL)-12, tumor necrosis factor-α, IL-6, and IL-1α production by monocytes as well as basal and phorbol 12-myristate 13-acetate plus ionomycin-stimulated interferon-γ, IL-4, and tumor necrosis factor-α production by T cells were determined on days 2, 5, and 10 postinjury and compared with similar measurements made in healthy control subjects.

Patients Twelve randomly selected black, male patients were enrolled in the study: mean injury severity score, 26; mean age, 35 yrs; mean Glasgow Coma Scale score, 13; systemic inflammatory response syndrome, 92%; sepsis, 42%; bronchial infection, 42%; and adult respiratory distress syndrome 25%.

Main Results After lipopolysaccharide stimulation, the number of IL-12-, tumor necrosis factor-α-, IL-1α-, and IL-6-producing CD14+ monocytes was 40% to 70% lower in trauma patients on postinjury days 2, 5, and 10 than in healthy control subjects. After phorbol 12-myristate 13-acetate stimulation, the number of IL-4-producing CD4+ cells increased three-fold in the trauma patients compared with healthy control subjects. In contrast, the number of interferon-γ- or tumor necrosis factor-α-producing CD4+ and CD8+ T cells was not different between the patients and control subjects. The Th1/Th2 ratio was significantly lower in patients on all postinjury days than in the control subjects. A statistically significant inverse correlation was found between the number of IL-12-producing monocytes and IL-4-producing CD4+ T cells in trauma patients (p = .007, r2 = .47). This correlation was absent in control subjects. The degree of depressed capacity of monocyte IL-12 production on day 2 postinjury showed a statistically significant correlation with the development of adult respiratory distress syndrome, sepsis, or infections and also with the duration of systemic inflammatory response syndrome and sepsis.

Conclusions Major trauma results in an early and marked decrease in monocyte cytokine-producing activity. The trauma-induced depression in IL-12 production by the mononuclear phagocyte system may promote T-cell commitment toward a Th2 pattern early after trauma. The appearance of the Th2 pattern is the result of elevated numbers of IL-4-producing cells without major alterations in T-cell interferon-γ-producing capacity. The degree of alterations in monocyte and T-cell responses on day 2 postinjury correlates with the development of adverse clinical outcomes and the subsequent duration of the inflammatory response.

From the Departments of Surgery (ZS, MS, JHS, EAD) and Pediatrics (ZCG, DSS, TD), New Jersey Medical School, Newark, NJ.

Supported, in part, by National Institute of General Medical Sciences National Institutes of Health grant GM-55005.

Address requests for reprints to: Zoltán Spolarics, MD, PhD, Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103. E-mail:

This study indicates that major trauma results in an early and sustained decrease in the number of monocytes capable of cytokine production that is accompanied by the differentiation of T-helper cells to the interleukin-4-producing phenotype.

© 2003 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins