Chapter 12 Cytokines Dec 21, 2006

Cytokines: Any of numerous secreted, low-molecular-weight (usually < 30 kDa) proteins or glycoproteins that regulate the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other effector cells. Role in cell-to-cell communication Messengers of the immune system

the Induction and Function of Cytokines Overview of the Induction and Function of Cytokines (can mediate biological effects at pM concentrations) (Kd ~ 10-10 to 10-12 M)

Most Cytokines Exhibit Autocrine and/or Paracrine Action; Fewer Exhibit Endocrine Action

Interaction of TH cells with macrophages, leading to release of numerous cytokines Although a variety of cells can secrete cytokines, the two principal producers are the TH cell and the macrophage.

How to keep the Ag-nonspecific cytokines from activating cells in a nonspecific fashion during an adaptive immune response ? Cytokine receptors are often expressed on a cell only after that cell has interacted with antigen. In this way, cytokine activation is limited to Ag-activated lymphocytes. Cytokines secreted at the junction of these interacting cells reach high enough local concentrations to affect the interacting cells, but not more distant cells. The half-life of cytokines is usually very short, ensuring that they act for only a limited period of time and thus over a short distance.

It should be kept in mind: 1. Most of the listed functions (Table 12-1) have been identified from analysis of the effects of recombinant cytokines, often at non-physiologic concentrations, added individually to in vitro system. 2. In vivo, however, cytokines rarely, if ever, act alone. 3. Instead, a target cell is exposed to a milieu (環境) containing a mixture of cytokines, whose combined synergistic or antagonistic effects can have very different consequences. 4. Cytokines often induce the synthesis of other cytokines, resulting in cascades of activity.

Cytokine Receptor Families (b) (c) (d) (e)

Subfamilies of Cytokine Receptors Have Signaling Subunits in Common

IL-2R Is the Most Thoroughly Studied Cytokine Receptor 3 Forms of the IL-2 Receptor (IL-2Ra = CD25) ( = TAC: T-cell activation)

Transduction Pathways JAK-STAT Signal Transduction Pathways of Cytokine Receptors JAK: Janus kinases STAT: signal tranducers and activators of transcription Janus : Roman god of gates and doors 兩面神

Cytokine Antagonists: IL-1Ra: IL-1 receptor antagonist Soluble cytokine receptors: sIL-2R, sIL-4R, sIL-6R, sIL-7R, sIFN-R, sTNF-R, sLIFR

TH1 and TH2 Responses of TH Cells TH1 response: produces a cytokine profile that supports inflammation and activates mainly certain T cells and macrophages. TH2 response: activates mainly B cells and immune responses that depend upon Ab.

- delayed-type hypersensitivity TH1 response: - delayed-type hypersensitivity - activation of TC cells - production of opsonization-promoting IgG Abs (i.e., Abs that bind to the high affinity FcRs of phagocytes and interact with complement, such as IgG2a in mice) - promotion of excessive inflammation and tissue injury

IFN-, a cytokine of the TH1 response: - activates macrophages - stimulates macrophages to a. increase microbicidal activity b. up-regulate the level of class II MHC c. secretes cytokines such as IL-12, which induces TH1 response - induces Ab class switching to IgG2a (mouse) or IgG1, 2, 3 (human) that supports phagocytosis and complement fixation - inhibits the expansion of the TH2 response

- promote the differentiation of fully cytotoxic TC IFN- and TNF- : - mediate inflammation - accounts for delayed hypersentivity IFN- and IL-2 : - promote the differentiation of fully cytotoxic TC cells from CD8+ precursors This pattern of cytokine production makes the TH1 subset particularly suited to respond to viral infections and intracellular pathogens.

TH2 response: - stimulates eosinophil activation and differentiation - provides help to B cells - promotes the production of relatively large amounts of IgM, IgE, and noncomplement-activating IgG isotypes - supports allergic reactions

IL-4, a cytokine of the TH2 response: - promotes Ab class switching to IgG1 (mouse) or IgG4 (human), which does not activate C - increases Ab class switching to IgE (combined with IL-5, promotes eosinophil activation) Typically, roundworm infections induce TH2 responses and evoke anti-roundworm IgE Ab. The Ab bound to the worm binds to the FceR of eosinophils, thus forming an Ag- specific bridge between the worm and the eosinophils. The attack of the eosinophil on the worm is triggered by cross- linking of the FceR-bound IgE.

Cytokine Environment Determines the Development of TH1 and TH2 Responses activated by intracellular pathogens and LPS IFNg IFNg cross regulation

T-Bet and GATA-3 play important roles in cross-regulation of TH responses