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Immunocytes Crosstalk Signaling Pathway

The activation stimulus (such as bacteria, viruses, fungi and parasites, as well as mechanical injury and toxic stimuli) leads to the immune response. It is called specific, because recognition molecules should ideally be specific for a single ligand. The cells responsible for these immune responses include monocyte, mast cell, macrophage, neutrophil, eosinophil, basophil, B and T lymphocyte. These cells secret cytokines which are small proteins providing cells with the ability to communicate with one another and orchestrate complex multicellular behavior, therefore regulating diverse functions in the immune response including proliferation, differentiation, migration and function of immunocytes.

The potency of cytokines, and the potential for amplification and damage which excessive cytokine production carries, has resulted in elaborate controls on cytokine production and action. Cytokines include interleukins (IL), interferons (IFN), chemokines, tumor necrosis factors (TNF) and growth factors that have been classified on the basis of their biological responses into pro- or anti-inflammatory catalogs, depending on their effects on immunocytes.

  • Interleukins (IL): a group of cytokines that were first seen to be expressed by leukocytes and acting on other leukocytes.
  • Interferons (IFN): a group of signaling proteins made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and also tumor cells.
  • Chemokines: a family of small cytokines, or signaling proteins to induce directed chemotaxis in nearby responsive cells.
  • Tumor necrosis factors (TNF): a group of signaling protein involved in systemic inflammation and exhibited cytotoxic effects on some cancer cell lines.
  • Growth factors: a group of subcellular substance capable of stimulating cellular growth, proliferation, and differentiation.

Many of the cytokines are not constitutively expressed in healthy adults, but are rapidly up-regulated in response to stimulation. And for many cells, cytokines are themselves potent cytokine inducers. Some, such as IL-1, TNF and IFNγ, are particularly potent inducers of cytokine gene expression, and are referred to as pro-inflammatory cytokines. Others, like IL-1 and TNF, are even capable of stimulating their own production. In addition to the many positive stimuli, several mediators act to limit or prevent cytokine gene expression, or to limit cytokine action. Examples include TGFβ, which is a broad-spectrum inhibitor of cytokine production, and IL-10, which is a potent inhibitor of TNF and IL-1 production by monocytes.

Immune responses are mediated by the binding of cytokines to specific receptors expressed on responding cells. However, complexity of cytokine effect commonly exits regarding to the following aspects: (a) Most cytokines have multiple effects on the same cell. For instance, cytokine IL-2 can trigger both proliferation and death in T cells, while TNFα or TGFβ can bind to more than one receptor which leads to diverse cellular response. (b) Many cytokines share receptor components and signaling intermediates but yet induce distinct responses in individual cells. The IL-6 and IL-12 family of cytokines, IL-2, IL-4, IL-9, IL-7, IL-15 and IL-21 share the common c-chain that are essential for signaling transduction. IL-12 and IL-23 share the same signaling chain, IL-12Rb2, and signaling pathway via JAK2 and STAT4. IL-2 and IL-15 share the common c-chain as well as the IL-2Rb chain (the specificity is resulted from a unique chain for each cytokine). (c) In addition, cytokines do not act in isolation. Instead, cells are exposed to various cytokines simultaneously or sequentially. Differences in the relative abundance of receptors or signaling intermediates may change how a cell responds to any given cytokine. Thus, it will be increasingly complex when attempting to understand an entire immune response involving several cell types and the cytokines they produce.

Cytokines are important in the communication between cells of multicellular organisms. They are pleiotropic intercellular mediators in controling the survival, growth, proliferation, differentiation and effector functions of cells, and play a key role in normal homeostatic tissue function as well as the regulation of the immune response, particularly during infections, inflammation, neurological and endocrinological autoimmune diseases.

References:

  • Morel PA, Lee RE, Faeder JR. Demystifying the cytokine network: Mathematical models point the way. Cytokine. 2016 Dec 3.
  • Dembic Z. The Cytokines of the Immune System: The Role of Cytokines in Disease Related to Immune Response. Academic Press; 2015 May 23.
  • Fitzgerald KA, O'Neill LA, Gearing AJ, Callard RE. The cytokine network-3.
  • Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nature Reviews Immunology. 2017 Jan 1;17(1):49-59.

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