Immune Cytokines

Cytokine Profile

about 38 total cytokines, including 18 interleukins, 5 interferons, 5 hematopoietins, 10 chemokines

cytokines mediate specific immunity (immune response involving B and T lymphocytes)

most cytokines have multiple activities (pleitrophism, separate pathways) that overlap (redundancy, shared pathways)

in other words, each cytokine affects different cells differently, and many cytokines can have the same activity

cytokines are clonally derived but differentiate to acquire a specific function

most cytokines have a variety of sources and targets (heterogeneity)

all cytokines are proteins; although most are secreted, almost all act locally

cytokines perform their functions through signal transduction (interaction with specific receptor

often oligomerize receptor

Regulation

cytokine production is inducible and self-limiting (i.e., negative feedback on its own production)

multiple cytokines can enhance or inhibit each other’s activity

additive – total activity is equal to sum of individual activities
syngeristic – total activity is more than sum of individual activities
antagonistic – total activity is less than either activity, sometimes no activity at all
saturable – total activity approaches a maximum, often equal to one of the individual activities

mechanisms of cross-regulation include modulating receptor expression or function

cytokines can be paracrine, autocrine, or (in a few cases, mostly those related to the innate response) endocrine

common cytokine inhibitor: soluble receptor (extracellular cytokine binding domain not bound to membrane)

binds cytokine in medium and thus competitively inhibits it
can act as cytokine antagonist to limit response

Classifications of Cytokines

hematopoietins (bone marrow) – many act alone

G-CSF, M-CSF, and GM-CSF (stimulates growth of granulocytes, macrophages, or both) – cannot activate differentiation alone

Epo (makes RBCs), TPO, IL-3, IL-9, IL-11

others enhance activities of other factors (TGF-b, TNF-a, IFN-g, IL-1, IL-4, IL-6)

chemokines – there are more of these in an inflammatory response than leukocytes

they are responsible for establishing the gradient that directs cells to the site of inflammation (closer to the inflammatory site, there will be more chemokines)

some attract neutrophils (IL-8, GRO a,b,g , MIP-2) – associated with bacterial infection

others attract all leukocytes (MIP-1a,b, RANTES, MCP-1,2,3,4)

pro-inflammatory – recruit innate cells prior to specific immune response – system puts inflammatory system on alert

include IL-1a, IL-1b, IL-6, TNFa

they are responsible for much of the pathology in sepsis (expression is too widespread)

anti-inflammatory – limit the inflammatory response

two essentially mutually exclusive T-cell responses

immunoregulatory (IL-2, IL-7, IL-12, IL-15) – cell mediated (e.g., delayed-type hypersensitivity (DTH)

counter-regulatory (IL-4, IL-10, IL-13, TGF-b) – IgE/Eosinophil based (e.g., allergy, immediate-type hypersens.)

immunoactive (immunoeffector) include IFN-g, IL-5, TNF-b

impacts the effector cell; clinical examples include leishmania and lysteria

Cytokine Structure

4-helix bundle family (IL-2, IL-4, GM-CSF, and HGH all display this)

receptor families include hematopoietic family and TNF receptor family

public chains – often one protein chain will be common to many cytokines (allows for redundancy and antagonism)

e.g., b c (IL-3, IL-5, GM-CSF); gp130 (IL-6, CNTF, LIF, IL-11, oncostatin-M); g c (IL-2, IL-4, IL-7, IL-9, IL-15)

Cytokines in Clinical Medicine

many cytokines have been implicated in disease

e.g., X-SCID is defect in the gc receptor chain, SCID is defect in JAK3 kinase associated with intracellular signaling

cytokines can be used therapeutically

e.g., Epo to correct anemia, G-CSF (neupogen) to correct neutrocytopenia, IFN-b to correct multiple sclerosis