[Frontiers in Bioscience 11, 272-299, January 1, 2006]

Contribution of anti-inflammatory/immune suppressive processes to the pathology of sepsis

Mario Perl, Chun-Shiang Chung, Megan Garber, Xin Huang, and Alfred Ayala

Division of Surgical Research, Department of Surgery, RI Hospital, Brown University Shcool of Medicine, Providence, RI 02903

FIGURES

Figure 1. Postulated inter-relationship of T-helper-cells (Th) (Th0-, Th1-, Th2-, Th3-cells), T-regulatory-cells (T-reg), gamma-delta-T-cells, natural-killer-T- (NKT) cell or cytotoxic-T-cell (Tc) -1 and -2 and the cytokines they express in the regulation/development of a competent cell-mediated immune response. See text for detailed description.

Figure 2. Aspects of the process of T-cell activation in the development of acquired immunity (either cell-mediated and/or humoral) in response to foreign antigen (Ag) presented by an antigen-presenting cell (APC). See text for detailed description.

Figure 3. Diagrammatic representation of the various activation signal pathways () induced by presentation of antigen (or mitogenic stimulant) through the T-cell receptor complex (TCR/CD3/CD4), in the presence or absence of co-stimulatory receptor signaling via CD28, various type I/II growth factors, chemokines, as well as a variety of antagonistic signals () which inhibit activation. Pathways that appear to be involved in transmitting signals, which both stimulate or inhibit cell activation, are indicated by (). For abbreviations please refer to text.

Figure 4. Diagram of some of the key components, mediators and the pathways, which have been implicated in the activation and suppression of immune cell apoptosis. In type I cells apoptosis is mainly induced via activation of the death receptor (extrinsic) pathway, in type II cells via the mitochondrial (intrinsic) pathway. The activation of apoptosis through the endoplasmatic reticulum might be considered as an additional route. Stats (Signal transducers and activators of transcription), PI3K (phosphatidylinositol-3 kinase), MAPKs (mitogen activated protein kinases), C/AIF (cellular apoptosis-inducing factor), ym (mitochondrial membrane potential), Apaf-1 (apoptosis-activating factor-1), MCL1 (myeloid cell leukemia sequence 1), FADD (Fas-associated death domain), TRADD (TNFR1-associated death domain), TRAF (TNFR associated factor), IAP (inhibitor of apoptosis proteins), RIP (receptor inhibitor protein), FLIP (FADD-like IL-1beta-converting enzyme (FLICE)-inhibitory protein), NF-kappa-B, nuclear factor-kappa-B.

Figure 5. Postulated steps (activation, antiinflammatory induced suppression, maladaptive intracellular signaling, pathologic induction of apoptosis) at which the process of immune cell (T-cell) activation/differentiation might be inhibited/suppressed by various agents leading to a resolution/suppression of the response to foreign antigen in T-lymphocytes following the onset of sepsis.

Figure 6. Postulated steps (activation, antiinflammatory induced suppression, maladaptive intracellular signaling, pathologic induction of apoptosis) at which the process of neutrophil activation/differentiation might be inhibited/suppressed by various agents leading to a suppression of the response of neutrophils to a foreign antigen following the onset of sepsis.

Figure 7. Postulated steps (activation, antiinflammatory induced suppression, maladaptive intracellular signaling, pathologic induction of apoptosis) at which the process of macrophage activation/differentiation might be inhibited/suppressed by various agents leading to the suppression of the response of macrophages to a foreign antigen following the onset of sepsis.