Section 19.7: Chemical Defenses - Cytokines

Cytokines

Cytokines are soluble proteins that act as communication signals between cells. In a nonspecific innate immune response, various cytokines may be released to stimulate production of chemical mediators or other cell functions, such as cell proliferation, cell differentiation, inhibition of cell division, apoptosis, and chemotaxis.

When a cytokine binds to its target receptor, the effect can vary widely depending on the type of cytokine and the type of cell or receptor to which it has bound. The function of a particular cytokine can be described as autocrine, paracrine, or endocrine (Figure \(\PageIndex{3}\)). In autocrine function, the same cell that releases the cytokine is the recipient of the signal; in other words, autocrine function is a form of self-stimulation by a cell. In contrast, paracrine function involves the release of cytokines from one cell to other nearby cells, stimulating some response from the recipient cells. Last, endocrine function occurs when cells release cytokines into the bloodstream to be carried to target cells much farther away.

Figure \(\PageIndex{3}\): Autocrine, paracrine, and endocrine actions describe which cells are targeted by cytokines and how far the cytokines must travel to bind to their intended target cells’ receptors.

Three important classes of cytokines are the interleukins, chemokines, and interferons. The interleukins were originally thought to be produced only by leukocytes (white blood cells) and to only stimulate leukocytes, thus the reasons for their name. Although interleukins are involved in modulating almost every function of the immune system, their role in the body is not restricted to immunity. Interleukins are also produced by and stimulate a variety of cells unrelated to immune defenses.

The chemokines are chemotactic factors that recruit leukocytes to sites of infection, tissue damage, and inflammation. In contrast to more general chemotactic factors, like complement factor C5a, chemokines are very specific in the subsets of leukocytes they recruit.

Interferons are a diverse group of immune signaling molecules and are especially important in our defense against viruses. Type I interferons (interferon-α and interferon-β) are produced and released by cells infected with virus. These interferons stimulate nearby cells to stop production of mRNA, destroy RNA already produced, and reduce protein synthesis. These cellular changes inhibit viral replication and production of mature virus, slowing the spread of the virus. Type I interferons also stimulate various immune cells involved in viral clearance to more aggressively attack virus-infected cells. Type II interferon (interferon-γ) is an important activator of immune cells (Figure \(\PageIndex{4}\)).

Figure \(\PageIndex{4}\): Interferons are cytokines released by a cell infected with a virus. Interferon-α and interferon-β signal uninfected neighboring cells to inhibit mRNA synthesis, destroy RNA, and reduce protein synthesis (top arrow). Interferon-α and interferon-β also promote apoptosis in cells infected with the virus (middle arrow). Interferon-γ alerts neighboring immune cells to an attack (bottom arrow). Although interferons do not cure the cell releasing them or other infected cells, which will soon die, their release may prevent additional cells from becoming infected, thus stemming the infection.

Inflammation-Eliciting Mediators

Many of the chemical mediators discussed in this section contribute in some way to inflammation and fever, which are nonspecific immune responses discussed in more detail in Inflammation and Fever. Cytokines stimulate the production of acute-phase proteins such as C-reactive protein and mannose-binding lectin in the liver. These acute-phase proteins act as opsonins, activating complement cascades through the lectin pathway.

Some cytokines also bind mast cells and basophils, inducing them to release histamine, a proinflammatory compound. Histamine receptors are found on a variety of cells and mediate proinflammatory events, such as bronchoconstriction (tightening of the airways) and smooth muscle contraction.

In addition to histamine, mast cells may release other chemical mediators, such as leukotrienes. Leukotrienes are lipid-based proinflammatory mediators that are produced from the metabolism of arachidonic acid in the cell membrane of leukocytes and tissue cells. Compared with the proinflammatory effects of histamine, those of leukotrienes are more potent and longer lasting. Together, these chemical mediators can induce coughing, vomiting, and diarrhea, which serve to expel pathogens from the body.

Certain cytokines also stimulate the production of prostaglandins, chemical mediators that promote the inflammatory effects of kinins and histamines. Prostaglandins can also help to set the body temperature higher, leading to fever, which promotes the activities of white blood cells and slightly inhibits the growth of pathogenic microbes (see Inflammation and Fever).

Another inflammatory mediator, bradykinin, contributes to edema, which occurs when fluids and leukocytes leak out of the bloodstream and into tissues. It binds to receptors on cells in the capillary walls, causing the capillaries to dilate and become more permeable to fluids.

Exercise \(\PageIndex{3}\)

1. What do the three complement activation pathways have in common?
2. Explain autocrine, paracrine, and endocrine signals.
3. Name two important inflammation-eliciting mediators.

Table \(\PageIndex{3}\) provides a summary of the chemical defenses discussed in this section.

Table \(\PageIndex{3}\): Chemical Defenses of Nonspecific Innate Immunity

Defense	Examples	Function
Chemicals and enzymes in body fluids	Sebum from sebaceous glands	Provides oil barrier protecting hair follicle pores from pathogens
	Oleic acid from sebum and skin microbiota	Lowers pH to inhibit pathogens
	Lysozyme in secretions	Kills bacteria by attacking cell wall
	Acid in stomach, urine, and vagina	Inhibits or kills bacteria
	Digestive enzymes and bile	Kill bacteria
	Lactoferrin and transferrin	Bind and sequester iron, inhibiting bacterial growth
	Surfactant in lungs	Kills bacteria
Antimicrobial peptides	Defensins, bacteriocins, dermicidin, cathelicidin, histatins,	Kill bacteria by attacking membranes or interfering with cell functions
Plasma protein mediators	Acute-phase proteins (C-reactive protein, serum amyloid A, ferritin, fibrinogen, transferrin, and mannose-binding lectin)	Inhibit the growth of bacteria and assist in the trapping and killing of bacteria
	Complements C3b and C4b	Opsonization of pathogens to aid phagocytosis
	Complement C5a	Chemoattractant for phagocytes
	Complements C3a and C5a	Proinflammatory anaphylatoxins
Cytokines	Interleukins	Stimulate and modulate most functions of immune system
	Chemokines	Recruit white blood cells to infected area
	Interferons	Alert cells to viral infection, induce apoptosis of virus-infected cells, induce antiviral defenses in infected and nearby uninfected cells, stimulate immune cells to attack virus-infected cells
Inflammation-eliciting mediators	Histamine	Promotes vasodilation, bronchoconstriction, smooth muscle contraction, increased secretion and mucus production
	Leukotrienes	Promote inflammation; stronger and longer lasting than histamine
	Prostaglandins	Promote inflammation and fever
	Bradykinin	Increases vasodilation and vascular permeability, leading to edema

Key Concepts and Summary

• Numerous chemical mediators produced endogenously and exogenously exhibit nonspecific antimicrobial functions.
• Many chemical mediators are found in body fluids such as sebum, saliva, mucus, gastric and intestinal fluids, urine, tears, cerumen, and vaginal secretions.
• Antimicrobial peptides (AMPs) found on the skin and in other areas of the body are largely produced in response to the presence of pathogens. These include dermcidin, cathelicidin, defensins, histatins, and bacteriocins.
• Plasma contains various proteins that serve as chemical mediators, including acute-phase proteins, complement proteins, and cytokines.
• The complement system involves numerous precursor proteins that circulate in plasma. These proteins become activated in a cascading sequence in the presence of microbes, resulting in the opsonization of pathogens, chemoattraction of leukocytes, induction of inflammation, and cytolysis through the formation of a membrane attack complex (MAC).
• Cytokines are proteins that facilitate various nonspecific responses by innate immune cells, including production of other chemical mediators, cell proliferation, cell death, and differentiation.
• Cytokines play a key role in the inflammatory response, triggering production of inflammation-eliciting mediators such as acute-phase proteins, histamine, leukotrienes, prostaglandins, and bradykinin.