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A. Definitions navigator

  1. Proteins involved in leukocyte (white blood cell) development and function
  2. Serve paracrine and autocrine functions
  3. Systemic (endocrine) levels of most cytokines are not detectable in healthy persons
  4. Families of Cytokines
    1. Proinflammatory - interleukin (IL) 1, IL12, IL18 and Interferon gamma families, TNF family
    2. Antiinflammatory - IL1 receptor antagonist, soluble receptors, IL10, IL4
    3. Glycoprotein 130 signalling cytokines - IL6, IL11, LIF, Oncostatin M, CNF
    4. Growth Factors - IL2, IL7, IL9, IL15; IL4 and IL12
    5. Fibrogenic Cytokines - transforming growth factor ß (TGFß), PDGF, FGF
    6. Antifibrogenic Cytokines - hepatocyte growth factor, IFN alpha and beta
    7. Antiviral Interferons IFNa and IFNb
    8. Chemokines - chemotactic cytokines, includes IL8, many others [19]

B. Interleukin 1 (IL1) navigator

  1. Source: macrophages (IL1 alpha and IL1 beta), monocytes
  2. Major Functions
    1. Activates T cells
    2. Differentiation and proliferation of B cells
    3. Stimulates inflammation, acute phase
    4. IL1-RA (IL1 receptor antagonist)
  3. Other Functions: macrophage stimulation, stimulates IL6 production
  4. Medical Utility
    1. IL1-RA (anakinra, Kineret®) moderately effective in rheumatoid arthritis
    2. Polymorphisms in IL1ß genes may predict cardiovascular events
    3. IL1 and IL1-RA polymorphisms may affect outcomes in sepsis, meningococcus [16]

C. Interleukin 2 (IL2) navigator

  1. Source: T helper (Th) cells, type 1 (Th 1)
  2. Major Functions: T cell growth factor, natural killer (NK) cell stimulation
  3. Other Functions: macrophage stimulation
  4. Medical Utility
    1. Immunotherapy (in vivo, ex vivo) for cancer (melanoma, renal cell)
    2. Adjunctive therapy in severe HIV infection

D. Interleukin 3 (IL3)navigator

  1. Source: bone marrow stromal cells, some T lymphocytes
  2. Major Functions: stimulation of early hematopoietic cell development
  3. Medical Utility: possibly in chemotherapy induced bone marrow failure

E. Interleukin 4 (IL4) navigator

  1. Source: CD4+ Th 2 cells, mast cells, basophils, eosinophils
  2. Major Functions
    1. Activation of Th 2 cells and monocytes
    2. Stimulation and activation of B cells, IgE class switching
    3. Inhibition of Th1 cell differentiation
    4. Stimulation of Th2 responses with IL13
  3. Other Functions
    1. IgG subclass switching; increases overall antibody production
    2. Stimulation of IL5 production by CD8+ T lymphocytes
    3. Inhibits proliferation of natural killer cells
  4. Medical Utility
    1. Antagonists may be useful in asthma and other allergic diseases
    2. Pitrakinra is an IL4/IL13 receptor antagonist
    3. Pitrakinra 60mg inhalation, but not 25mg subcutaneously, reduced allergen induced bronchoconstriction by 3.7 fold in patients with atopic asthma [8]

F. Interleukin 5 (IL5) navigator

  1. Source: CD4+ Th 2 cells, CD8+ T cells, mast cells, eosinophils
  2. Major Functions: eosinophil differentiation, proliferation, chemoattraction
  3. Medical Utility
    1. Antagonists reduce eosinophil counts
    2. However, no effect of anti-IL5 antibodies on asthma [4,5]
    3. Antagonists may be useful in other eosinophil associated diseases

G. Interleukin 6 (IL6) navigator

  1. Source: Th 2 cells, macrophages, activated endothelium
  2. Major Functions
    1. Lymphocyte maturation and activation
    2. B cell differentiation, increases IgG1 and IgA
    3. Acute phase inflammatory responses: induces TNFa and IL1 production
    4. Associated with chronic inflammation, stimulation of C-reactive protein (CRP)
  3. Other Functions: growth factor for myeloma, some lymphomas, monoclonal gammopathies
  4. Medical Utility
    1. Inhibition may be useful in certain cancers such as myeloma, Castleman's
    2. Elevated levels associated with frailty and functional decline in elderly [15]
    3. Elevated levels likely responsible for driving increased CRP levels in vascular disease

H. Interleukin 7 (IL7)navigator

  1. Source: bone marrow stromal cells
  2. Major Functions: proliferation of pre-B cells and progenitors
  3. Minor Functions: proliferation of activated T cells
  4. Medical Utility: B cell stimulation in acquired or congenital immunodeficiency

I. Interleukin 8 (IL8) navigator

  1. Source: macrophages, T cells
  2. Major Functions: neutrophil, basophil and T cell chemotaxis
  3. Medical Utility: levels may correlate with degree of neutrophilia

J. Interleukin 9navigator

  1. Source: T lymphocytes, primarily Th2 cells
  2. Major Functions: enhance response of B cells to IL4
  3. Medical Utility: inhibition may have activity in B cell dysfunction

K. Interleukin 10navigator

  1. Source: All T lymphyoctes (Th0, Th1, Th2 and CD8+), some accessory cells
  2. Major Functions: antiinflammatory, inhibits macrophage activation
  3. Minor Functions: stimulates differentiation of monocytes to macrophages
  4. Medical Utility
    1. IL10 or agonist may have efficacy in autoimmune and inflammatory diseases
    2. IL10 promotor polymorphism of prognostic utility in graft-versus-host disease [17]

L. Interleukin 11 (IL11) navigator

  1. Source: bone marrow stromal cells
  2. Major Functions: stimulation of acute phase protein production
  3. Other Functions
  4. Stimulation of platelet development
  5. Stimulates B cell differentiation and activation
  6. Maintenance of gut epithelial integrity (in setting of chemotherapy / neutropenia) [14]
  7. Medical Utility: reduce chemotherapy induced thrombocytopenia

M. Interleukin 12 (IL12) navigator

  1. Source: monocytes, macrophages and B cells; heterodimer p40/p30
  2. Major Functions
    1. Induction of Th 1 cells from Th0 cells and production of IL2
    2. stimulation of Th 1 and NK cell IFN gamma
  3. Other Functions: suppression of Th 2 cells, activates natural killer cells
  4. Medical Utility
    1. Immunostimulant with possible vaccine adjuvant, possible uses in oncology
    2. Immunomodulator to switch Th2 to Th1 responses
    3. Given subcutaneously, reduces periperhal and sputum eosinophils in asthmatic patients [6]
    4. No effect, however, on airway hyperresponsiveness in asthma [6]
  5. Anti-IL-12 Ab in Crohn's Disease [18]
    1. Two doses of 3mg/kg subcutaneously induced responses (75%) and remissions in CD
    2. Anti-IL-12 Ab also reduced local levels of IL-12, IFNg, TNFa, and IL6
    3. Induction of remission is rapid and remission can be sustained for 18 weeks
    4. Very well tolerated with only increased localized reactions compared with placebo
  6. Anti-IL12/23 Ab significantly improved moderate to severe plaque psoriasis [21]

N. Interleukin 13navigator

  1. Source: CD4+ Th2 cells
  2. Major Functions: similar to IL4 on B and T cells (see above)
  3. Minor Functions: Blocks IL1 and TNFa production from monocytes
  4. Medical Utility
    1. Inhibition may have efficacy in allergic or autoimmune diseases
    2. Pitrakinra is an IL4/IL13 receptor antagonist
    3. Pitrakinra 60mg inhalation, but not 25mg subcutaneously, reduced allergen induced bronchoconstriction by 3.7 fold in patients with atopic asthma [8]

O. Interleukin 14navigator

  1. Source: activated T cells
  2. Major Functions: expansion of B cells, inhibition of immunoglobulin synthesis
  3. Medical Utility: unknown

P. Interleukin 15navigator

  1. Source: monocytes, macropahges
  2. Major Functions: stimulates cytotoxicity of T cells and natural killer cells
  3. Minor Functions: stimulates expression of intracellular adhesion molecule 3 (ICAM-3)
  4. Medical Utility: possible immunostimulant

Q. Interleurin 16navigator

  1. Source: CD8+ T cells
  2. Major Functions: growth factor and chemoattractant for CD4+ T cells
  3. Medical Utility: unknown

R. Interleukin 17navigator

  1. Source: CD4+ memory cells, Th17 cells
  2. Major Functions
    1. Proliferation and activation of autocrine factors
    2. Appears to be important for
  3. Medical Utility: antibodies may block Th1 immune disease

S. Interleukin 18 navigator

  1. Source: macrophages
  2. Major Functions
    1. Proinflammatory very early in Th1 immune responses [20]
    2. IFN gamma inducing factor in T cells
  3. Minor Functions: inhibits IgE production by increasing IFN gamma
  4. Medical Utility: unknown

T. Interleukin 23 [21] navigator

  1. Source: Th1 CD4+ T cells
  2. Major Functions
    1. Proinflammatory Th1 cytokine
    2. Shares p40 subunit with IL12, has unique p19 subunit
    3. Overexpressed in psoriasis, other inflammatory dermatologic lesions
  3. Minor Functions: unknown
  4. Medical Utility: antibodies to IL12/IL23 of significant benefit in psoriasis [21]

U. Tumor Necrosis Factor alpha (TNFa) [10] navigator

  1. Source: macropages, NK cells, lymphocytes, mast cells
  2. Major Functions [3]
    1. Initiation and promotion of inflammation
    2. Pro- or anti-apoptotic depending on situation
  3. Other Functions
    1. Induction of IL1 and IL6
    2. Perpetuation of inflammation in Crohn's Disease
    3. Perpetuation of inflammation in Rheumatoid Arthritis
  4. Medical Utility
    1. Blockade of TNFa or its receptor effective in various autoimmune diseases
    2. TNFa promoter polymorphisms associated with increased risk of various diseases [9]
    3. TNFa-2 allele associated with elevated levels of serum TNFa and death in septic shock [11]

V. TNFß (Lymphotoxin)navigator

  1. Source: Th 1 cells and B cells
  2. Major Functions: promotion of inflammation
  3. Other Functions: may play a role in pathogenesis of autoimmune diseases
  4. Medical Utility: blockade may be useful in certain autoimmune diseases

W. Transforming Growth Factor ß (TGFß)navigator

  1. Source: lymphocytes, macrophages, mast cells
  2. Major Functions: promotion of connective tissue
  3. Other Functions: immune suppression (both Th 1 and Th 2 responses)
  4. Medical Utility: may be useful in certain autoimmune diseases
  5. TGFß family of dimeric cytokines with conserved sequence structures [12]
    1. TFGß1, ß2, ß3
    2. Macrophage inhibitory cytokine (MIC-1)
    3. Other cytokines involved in normal development

X. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)navigator

  1. Source: lymphocytes, macrophages, NK cells
  2. Major Functions: promotes growth of neutrophils and macrophages
  3. Other Functions: stimulation of bone marrow progenitor cells
  4. Medical Utility
  5. Reduction of chemotherapy induced neutropenia and bone marrow transplants
  6. Induction of remission of Crohn's Disease in patients with moderate to severe disease [13]

Y. Granulocyte Colony Stimulating Factor (G-CSF) navigator

  1. Source: T lymphocytes, other cells
  2. Major Functions: stimulation of neutrophil differentiation and development
  3. Medical Utility: chemotherapy induced neutropenia, other neutropenia

Z. Stem Cell Factor (SCF, c-Kit Ligand, ancastim)navigator

  1. Source: bone marrow stroma, fibroblasts
  2. Major Functions: multipotential stem cell stimulation
  3. Minor Functions: mast cell stimulation, chemoattraction
  4. Medical Utility: restoration of multiple lineages following chemotherapy [2]
AA. Interferons

References navigator

  1. Delves PJ and Roitt IM. 2000. NEJM. 343(2):108 abstract
  2. Blaise D, Faucher C, Vey N, et al. 2000. Lancet. 356(9138):1325
  3. Tilg H and Diehl AM. 2000. NEJM. 343(20):1467 abstract
  4. Leckie MJ, ten Brinke A, Khan J, et al. 2000. Lancet. 356(9248):2144 abstract
  5. Kips JC, O'Connor BJ, Langley SJ, et al. 2000. Am J Respir Crit Care Med. 161A:505
  6. Bryan SA, O'Connor BJ, Matti S, et al. 2000. Lancet. 356(9248):2149 abstract
  7. Busse WW and Lemanske RF. 2001. NEJM. 344(5):350 abstract
  8. Wenzel S, Willraham D, Fuller R, et al. 2007. Lancet. 370(9596):1422 abstract
  9. McCusker SM, Curran MD, Dynan KB, et al. 2001. Lancet. 357(9254):436 abstract
  10. Choy EHS and Panayi GS. 2001. NEJM. 344(12):907 abstract
  11. Appoloni O, Dupont E, Vandercruys M, et al. 2001. Am J Med. 110(6):486 abstract
  12. Brown DA, Breit SN, Buring J, et al. 2002. Lancet. 359(9324):2159 abstract
  13. Dieckgraefe BK and Korzenik JR. 2002. Lancet. 360(9344):1478 abstract
  14. Ellis M, Zwaan F, Hedstrom U, et al. 2003. Lancet. 361(9354):275 abstract
  15. Cohen HJ, Harris T, Pieper CF. 2003. Am J Med. 114(3):180 abstract
  16. Read RC, Cannings C, Naylor SC, et al. 2003. Ann Intern Med. 138(7):534 abstract
  17. Lin MT, Storer B, Martin PJ, et al. 2003. NEJM. 349(23):2201 abstract
  18. Mannon PJ, Fuss IJ, Mayer L, et al. 2004. NEJM. 351(20):2069 abstract
  19. Charo IF and Ransohoff RM. 2006. NEJM. 354(6):610 abstract
  20. Shmerling RH. 2006. JAMA. 295(21):2525 abstract
  21. Krueger GG, Langley RG, Leonardi C, et al. 2007. NEJM. 356(6):580 abstract