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Immunology Chapter 13. Richard L. Myers, Ph.D. Department of Biology Southwest Missouri State Temple Hall 227 Telephone: 417-836-5307 Email: rlm967f@mail.smsu.edu Homepage: http://creative.smsu.edu/biology/myersr/index.html TopClass: http://creative.smsu.edu. Cytokines.
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ImmunologyChapter 13 • Richard L. Myers, Ph.D. • Department of Biology • Southwest Missouri State • Temple Hall 227 • Telephone: 417-836-5307 • Email: rlm967f@mail.smsu.edu • Homepage: http://creative.smsu.edu/biology/myersr/index.html • TopClass: http://creative.smsu.edu
Cytokines • A group of low molecular weight compounds control communication between lymphoid, inflammatory and hematopoietic cells • collectively called cytokines • for cell-to-cell communication • sometimes called immune hormones • Regulatory proteins that bind to specific receptors on the surface of target cells • elicit biochemical changes • alters the pattern of gene expression in targets
Cytokine activities • Autocrine action • binding to the membrane of the secreting cell • Paracrine action • binding to receptors on a close target cell • Endocrine action • binding to target cells in distant parts of the body
Regulation by cytokines • Pleiotropy • different biological effects on different cells • Redundancy • two or more cytokines mediate same function • Synergy • combined effect is greater than either alone • Antagonism • one offsets effects of another
Interleukins and other cytokines • Many cytokines are called interleukins • because they are secreted by leukocytes • and act upon other leukocytes • there are approximately 20 identified to date • Other cytokines known by a common name • interferons • tumor necrosis factors
Function of cytokines • Generally function as intracellular messenger molecules • evoke a specific biological activity • Two principle producers are macrophages and TH cells • Rarely act alone but with many others • Often induce the synthesis of other cytokines
When a cytokine binds to its receptor, it induces numerous physiological responses • development of cellular and humoral immune responses • induction of the inflammatory response • regulation of hematopoiesis • control of cellular proliferation and differentiation • induction of wound healing
Cytokine receptor families or Class I IFN-a,b,g Interferon or Class II
IL-2 receptor • Three chain structure • Has a, b and g chains • Expressed on activated T cells in three forms • low affinity • intermediate affinity • high affinity
IL-2 facts • Most studied of cytokine receptors • Chain a has different structure • expressed only by activated cells • referred to as T-cell activation (TAC) antigen • Signal transduction requires both b and g • CD4 and CD8 express high-affinity IL-2 receptors and proliferate in response to IL-2
Cytokine signal transduction • Recently, a unifying model was proposed • Class I and II signal because of a cytokine induced dimerization of receptor subunits • allows for engagement of intracellular signaling machinery • Then JAK kinases (tyrosine kinases) interact with dimerized receptors • these phosphorylate each other and transcription factors (STATs) • STATs translocate to the nucleus and activate gene transcription
Signal transduction • Binding induces dimerization • JAK interacts with tyrosine kinases and phosphorylates kinases • Also STAT transcription factors • STATs dimerize and translocate to nucleus • Activate transcription of specific genes See Fig 13-9 Kuby
Cytokines and disease • Defects in cytokine regulatory networks have been implicated in disease • overexpression • underexpression • A variety of cytokine abnormalities may lead to disease
Bacterial septic shock • Results from overproduction of cytokines • By gram-negative cells • Symptoms include • drop in blood pressure • fever • diarrhea • blood clotting • LPS causes macrophages to overproduce IL-1 and TNF-a
Bacterial toxic shock • Some microorganisms produce toxins that act as “superantigens” • Staphylococcus aureus is a good example • It produces several superantigens like enterotoxins, exfoliating and TSST-1 toxins • Excessive activation of T cells produce excess cytokine
Superantigen binding • Superantigens bind simultaneously to a class II MHC and to the Vb domain of the TCR • They are not internalized, processed and presented by APCs • Binding is outside of the binding cleft • They can activate large numbers of T cells irrespective of specificity
Superantigens bind to MHCs • Crystal structures show that molecules like TSST-1 bind to a chains of class II MHCs • Binding of superantigen does not interfere with antigen binding site
Others • Cytokines may be produced in different levels in some types of cancer • IL-6 overproduction in cardiac myxoma, myeloma, cervical and bladder cancer cells • Trypanosoma cruzi will cause Chagas’ disease • immunosuppression results because the a subunit of the IL-2 receptor is not made
Assignment • Read Chapter 14, Complement • Review question 5 (pg 355)