Doxycycline

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Doxycycline 

 

Doxycycline

Clinical data
Pronunciation	/ˌdɒksɪˈsaɪkliːn/ DOKS-i-SY-kleen
Trade names	Doryx, Doxyhexal, Doxylin among others
AHFS/Drugs.com	Monograph
MedlinePlus	a682063
License data	US DailyMed: Doxycycline US FDA: Doxycycline
Pregnancy category	AU: D
Routes of administration	By mouth, IV
ATC code	J01AA02 (WHO) A01AB22 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	~100%
Protein binding	80–90%
Metabolism	Negligible
Elimination half-life	10–22 hours
Excretion	Mainly faeces, 40% urine
Identifiers

IUPAC name
CAS Number	564-25-0
PubChem CID	Doxycycline
DrugBank	DB00254
ChemSpider	10482106
UNII	334895S862
KEGG	D00307
ChEBI	CHEBI:60648
ChEMBL	ChEMBL1433
CompTox Dashboard (EPA)	DTXSID0037653
ECHA InfoCard	100.008.429
Chemical and physical data
Formula	C22H24N2O8
Molar mass	444.440 g·mol−1
3D model (JSmol)	Interactive image

SMILES

InChI

Doxycycline is a broad-spectrum tetracycline-class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, and syphilis. It is also used to prevent malaria and in combination with quinine, to treat malaria. Doxycycline may be taken by mouth or by injection into a vein.

Common side effects include diarrhea, nausea, vomiting, and an increased risk of sunburn. Use after the first trimester of pregnancy or in young children may result in permanent discoloration of the teeth. Its use during breastfeeding is probably safe. Doxycycline is a broad-spectrum antibiotic, of the tetracycline class. Use of any antibiotic has been shown to increase a person's risk of multiple sclerosis, with a relative risk that depends on the class of antibiotic; tetracyclines increase a person's risk of MS by an average of 33%. Like other agents of the tetracycline class, it either slows or kills bacteria by inhibiting protein production. It kills malaria by targeting a plastid organelle, the apicoplast.

Doxycycline was patented in 1957 and came into commercial use in 1967. It is on the World Health Organization's List of Essential Medicines. Doxycycline is available as a generic medicine. In 2018, it was the 80th most commonly prescribed medication in the United States, with more than 10 million prescriptions. It is available in India under the brand name DOXY-1- LDR.

Medical use

Generic 100 mg doxycycline capsules

 

Doxycycline package

In addition to the general indications for all members of the tetracycline antibiotics group, doxycycline is frequently used to treat Lyme disease, chronic prostatitis, sinusitis, pelvic inflammatory disease, acne, rosacea, and rickettsial infections.

In Canada, in 2004, doxycycline was considered a first-line treatment for chlamydia and non-gonococcal urethritis and with cefixime for uncomplicated gonorrhea.

Antibacterial

Moraxella catarrhalis, Brucella melitensis, Chlamydia pneumoniae, and Mycoplasma pneumoniae are generally susceptible to doxycycline, while some Haemophilus spp., Mycoplasma hominis, and Pseudomonas aeruginosa have developed resistance to varying degrees.

It is used in the treatment and prophylaxis of anthrax and Leptospirosis. It is also effective against Yersinia pestis (the infectious agent of bubonic plague), and is prescribed for the treatment of Lyme disease, ehrlichiosis, and Rocky Mountain spotted fever.

Doxycycline is indicated for treatment of:

• Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsia
• Respiratory tract infections caused by Mycoplasma pneumoniae
• Lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis
• Psittacosis
• Nongonococcal urethritis caused by Ureaplasma urealyticum
• Relapsing fever due to Borrelia recurrentis
• Chancroid caused by Haemophilus ducreyi
• Plague due to Yersinia pestis
• Tularemia
• Cholera
• Campylobacter fetus infections
• Brucellosis caused by Brucella species (in conjunction with streptomycin)
• Bartonellosis
• Granuloma inguinale (Klebsiella species)
• Lyme disease

When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-negative bacteria:

• Escherichia coli infections
• Enterobacter aerogenes (formerly Aerobacter aerogenes) infections
• Shigella species infections
• Acinetobacter species (formerly Mima species and Herellea species) infections
• Respiratory tract infections caused by Haemophilus influenzae
• Respiratory tract and urinary tract infections caused by Klebsiella species

Some Gram-positive bacteria have developed resistance to doxycycline. Up to 44% of Streptococcus pyogenes and up to 74% of S. faecalis specimens have developed resistance to the tetracycline group of antibiotics. Up to 57% of P. acnes strains developed resistance to doxycycline. When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-positive bacteria:

• Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae)
• Skin and soft tissue infections caused by Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus infections
• Anthrax caused by Bacillus anthracis infection

When penicillin is contraindicated, doxycycline can be used to treat:

• Syphilis caused by Treponema pallidum
• Yaws caused by Treponema pertenue
• Listeriosis due to Listeria monocytogenes
• Vincent's infection caused by Fusobacterium fusiforme
• Actinomycosis caused by Actinomyces israelii
• Infections caused by Clostridium species

Doxycycline may also be used as adjunctive therapy for severe acne.

The first-line treatment for brucellosis is a combination of doxycycline and streptomycin and the second-line is a combination of doxycycline and rifampicin (rifampin).

Antimalarial

Doxycycline is active against the erythrocytic stages of Plasmodium falciparum but not against the gametocytes of Plasmodium falciparum. It is used to prevent malaria. It is not recommended alone for initial treatment of malaria, even when the parasite is doxycycline-sensitive, because the antimalarial effect of doxycycline is delayed.

The World Health Organization (WHO) guidelines state that the combination of doxycycline with either artesunate or quinine may be used for the treatment of uncomplicated malaria due to Plasmodium falciparum or following intravenous treatment of severe malaria.

Antihelminthic

Doxycycline kills the symbiotic Wolbachia bacteria in the reproductive tracts of parasitic filarial nematodes, making the nematodes sterile, and thus reducing transmission of diseases such as onchocerciasis and elephantiasis. Field trials in 2005 showed an eight-week course of doxycycline almost completely eliminates the release of microfilariae.

Spectrum of susceptibility

Doxycycline has been used successfully to treat sexually transmitted, respiratory, and ophthalmic infections. Representative pathogenic genera include Chlamydia, Streptococcus, Ureaplasma, Mycoplasma, and others. The following represents MIC susceptibility data for a few medically significant microorganisms.

• Chlamydia psittaci: 0.03 μg/mL
• Mycoplasma pneumoniae: 0.016 μg/mL — 2 μg/mL
• Streptococcus pneumoniae: 0.06 μg/mL — 32 μg/mL

Sclerotherapy

Doxycycline is also used for sclerotherapy in slow-flow vascular malformations, namely venous and lymphatic malformations, as well as post-operative lymphoceles.

Others

Subantimicrobial-dose doxycycline (SDD) is widely used as an adjunctive treatment to scaling and root planing for periodontitis. Significant differences were observed for all investigated clinical parameters of periodontitis in favour of the scaling and root planing + SDD group where SDD dosage regimens is 20 mg twice daily for 3 months in a meta analysis published in 2011.

Contraindications

Pregnancy and lactation

Doxycycline is categorized by the FDA as a class D drug in pregnancy. Doxycycline crosses into breastmilk. Other tetracycline antibiotics are contraindicated in pregnancy and up to eight years of age, due to the potential for disrupting bone and tooth development. They include a class warning about staining of teeth and decreased development of dental enamel in children exposed to tetracyclines in utero, during breastfeeding or during young childhood. However, the FDA has acknowledged that the actual risk of dental staining of primary teeth is undetermined for doxycycline specifically. The best available evidence indicates that doxycycline has little or no effect on hypoplasia of dental enamel or on staining of teeth and the CDC recommends the use of doxycycline for treatment of Q fever and also for tick-borne rickettsial diseases in young children and others advocate for its use in malaria.

Other

Other contraindications are severe liver disease and concomitant use of isotretinoin or other retinoids, as both tetracyclines and retinoids can cause intracranial hypertension (increased pressure around the brain) in rare cases.

Adverse effects

Adverse effects are similar to those of other members of the tetracycline antibiotic group. Doxycycline can cause gastrointestinal upset. Oral doxycycline can cause pill esophagitis, particularly when it is swallowed without adequate fluid, or by persons with difficulty swallowing or impaired mobility. Doxycycline is less likely than other antibiotic drugs to cause Clostridium difficile colitis.

An erythematous rash in sun-exposed parts of the body has been reported to occur in 7.3–21.2% of persons taking doxycycline for malaria prophylaxis. One study examined the tolerability of various malaria prophylactic regimens and found doxycycline did not cause a significantly higher percentage of all skin events (photosensitivity not specified) when compared with other antimalarials. The rash resolves upon discontinuation of the drug.

Unlike some other members of the tetracycline group, it may be used in those with renal impairment.

Doxycycline use has been associated with increased risk of inflammatory bowel disease. In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohn's disease.

Interactions

The combination of doxycycline with dairy, antacids, calcium supplements, iron products, laxatives containing magnesium, or bile acid sequestrants is not inherently dangerous, but any of these foods and supplements may decrease doxycycline's effectiveness.

Breakfast was observed to reduce doxycycline absorption significantly. Absorption of tetracycline occurs in the stomach and the upper small intestine. Absorption of tetracyclines has been reported to be impaired by milk products, aluminum hydroxide gels, sodium bicarbonate, calcium and magnesium salts, laxatives containing magnesium and iron preparations. The mechanisms responsible for decreased absorption appear to be chelation and an increase in gastric pH. ... In view of these results, it is advisable to instruct the patients to take doxycycline on an empty stomach.

Previously, doxycycline was believed to impair the effectiveness of many types of hormonal contraception due to CYP450 induction. Research has shown no significant loss of effectiveness in oral contraceptives while using most tetracycline antibiotics (including doxycycline), although many physicians still recommend the use of barrier contraception for people taking the drug to prevent unwanted pregnancy.

Pharmacology

Doxycycline, like other tetracycline antibiotics, is bacteriostatic. It works by preventing bacteria from reproducing through the inhibition of protein synthesis.

Doxycycline is highly lipophilic so can easily enter cells, meaning the drug is easily absorbed after oral administration and has a large volume of distribution. It can also be re-absorbed in the renal tubules and gastrointestinal tract due to its high lipophillicity so has a long elimination half life, and does not accumulate in the kidneys of patients with kidney failure due to the compensatory excretion in faeces. Doxycycline–metal ion complexes are unstable at acid pH, therefore more doxycycline enters the duodenum for absorption than the earlier tetracycline compounds. In addition, food has less effect on absorption than on absorption of earlier drugs with doxycycline serum concentrations being reduced by about 20% by test meals compared with 50% for tetracycline.

Mechanism of action

Doxycycline is a broad spectrum antibiotic. It inhibits the synthesis of bacterial proteins by binding to the 30S ribosomal subunit, which is only found in bacteria. This prevents the binding of transfer RNA to messenger RNA at the ribosomal subunit meaning amino acids cannot be added to polypeptide chains and new proteins cannot be made. This stops bacterial growth giving the immune system time to kill and remove the bacteria.

Pharmacokinetics

The substance is almost completely absorbed from the upper part of the small intestine. It reaches highest concentrations in the blood plasma after one to two hours and has a high plasma protein binding rate of about 80–90%. Doxycycline penetrates into almost all tissues and body fluids. Very high concentrations are found in the gallbladder, liver, kidneys, lung, breast milk, bone and genitals; low ones in saliva, aqueous humour, cerebrospinal fluid (CSF), and especially in inflamed meninges. By comparison, the tetracycline antibiotic minocycline penetrates significantly better into the CSF and meninges.

Doxycycline metabolism is negligible. It is actively excreted into the gut (in part via the gallbladder, in part directly from blood vessels), where some of it is inactivated by forming chelates. About 40% are eliminated via the kidneys, much less in people with end-stage kidney disease. The biological half-life is 18 to 22 hours (16±6 hours according to another source) in healthy people, slightly longer in those with end-stage kidney disease, and significantly longer in those with liver disease.

Chemistry

Expired tetracyclines or tetracyclines allowed to stand at a pH less than 2 are reported to be nephrotoxic due to the formation of a degradation product, anhydro-4-epitetracycline causing Fanconi syndrome. In the case of doxycycline, the absence of a hydroxyl group in C-6 prevents the formation of the nephrotoxic compound. Nevertheless, tetracyclines and doxycycline itself have to be taken with caution in patients with kidney injury, as they can worsen azotemia due to catabolic effects.

Chemical properties

Doxycycline, doxycycline monohydrate and doxycycline hyclate are yellow, crystalline powders with a bitter taste. The latter smells faintly of ethanol; a 1% aqueous solution has a pH of 2–3; and the specific rotation is ${\displaystyle [\alpha ]_{D}^{25}}$ −110° cm³/dm·g in 0.01 N methanolic hydrochloric acid.

Solubility

Solubility in	Doxycycline	Doxycycline monohydrate	Doxycycline hyclate
Water	very slightly	very slightly	freely
Ethanol	very slightly	very slightly	sparingly
Aqueous acids	freely	freely
Alkali hydroxyde solutions	freely	freely
Chloroform	very slightly	practically insoluble	practically insoluble
Diethyl ether	insoluble	practically insoluble	practically insoluble

History

After penicillin revolutionized the treatment of bacterial infections in WWII, many chemical companies moved into the field of discovering antibiotics by bioprospecting. American Cyanamid was one of these, and in the late 1940s chemists there discovered chlortetracycline, the first member of the tetracycline class of antibiotics. Shortly thereafter, scientists at Pfizer discovered terramycin and it was brought to market. Both compounds, like penicillin, were natural products and it was commonly believed that nature had perfected them, and further chemical changes could only degrade their effectiveness. Scientists at Pfizer led by Lloyd Conover modified these compounds, which led to the invention of tetracycline itself, the first semi-synthetic antibiotic. Charlie Stephens' group at Pfizer worked on further analogs and created one with greatly improved stability and pharmacological efficacy: doxycycline. It was clinically developed in the early 1960s and approved by the FDA in 1967.

As its patent grew near to expiring in the early 1970s, the patent became the subject of lawsuit between Pfizer and International Rectifier that was not resolved until 1983; at the time it was the largest litigated patent case in US history. Instead of a cash payment for infringement, Pfizer took the veterinary and feed-additive businesses of International Rectifier's subsidiary, Rachelle Laboratories.

In January 2013, the FDA reported shortages of some, but not all, forms of doxycycline "caused by increased demand and manufacturing issues". Companies involved included an unnamed major generics manufacturer that ceased production in February 2013, Teva (which ceased production in May 2013), Mylan, Actavis, and Hikma Pharmaceuticals. The shortage came at a particularly bad time, since there were also shortages of an alternative antibiotic, tetracycline, at the same time. The market price for doxycycline dramatically increased in the United States in 2013 and early 2014 (from $20 to over $1800 for a bottle of 500 tablets), before decreasing again.

Society and culture

Doxycycline is available worldwide under many brand names. Doxycycline is available as a generic medicine.

Research

In chronic obstructive pulmonary disease, doxycycline has been shown to improve lung functions in people with stable symptoms.

Other experimental applications include:

• Macular degeneration
• Vancomycin-resistant enterococcus
• Infected animal bite wounds (Pasteurella multocida, Pasteurella pneumotropica)
• Rheumatoid arthritis instead of minocycline (both of which have demonstrated modest efficacy for this disease)
• Chronic inflammatory lung diseases (panbronchiolitis, asthma, cystic fibrosis, bronchitis). Both doxycycline and minocycline have shown effectiveness in asthma due to immune suppressing effects.
• Sarcoidosis
• Idiopathic pulmonary fibrosis
• Wound healing

Tet-ON inducible shRNA system

Research reagent

Doxycycline and other members of the tetracycline class of antibiotics are often used as research reagents in in vitro and in vivo biomedical research experiments involving bacteria as well in experiments in eukaryotic cells and organisms with inducible protein expression systems using tetracycline-controlled transcriptional activation. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however protein translation is also disrupted in eukaryotic mitochondria impairing metabolism and leading to effects that can confound experimental results. Doxycycline is also used in "tet-on" (gene expression activated by doxycycline) and "tet-off" (gene expression inactivated by doxycycline) tetracycline-controlled transcriptional activation to regulate transgene expression in organisms and cell cultures. Doxycycline is more stable than tetracycline for this purpose. At subantimicrobial doses, doxycycline is an inhibitor of matrix metalloproteases, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions.

Cytokine storm

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cytokine_storm 

Cytokine storm
Other names	hypercytokinemia
Specialty	Immunology

A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Normally, cytokines are part of the body's immune response to infection, but their sudden release in large quantities can cause multisystem organ failure and death. Cytokine storms can be caused by a number of infectious and non-infectious etiologies, especially viral respiratory infections such as H1N1 influenza, H5N1 influenza, SARS-CoV-1, and SARS-CoV-2 (COVID-19 agent). Other causative agents include the Epstein-Barr virus, cytomegalovirus, group A streptococcus, and non-infectious conditions such as graft-versus-host disease. The viruses can invade lung epithelial cells and alveolar macrophages to produce viral nucleic acid, which stimulates the infected cells to release cytokines and chemokines, activating macrophages, dendritic cells, and others.

Cytokine storm syndrome is a diverse set of conditions that can result in a cytokine storm. Cytokine storm syndromes include familiar hemophagocytic lymphohistiocytosis, Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis, systemic or non-systemic juvenile idiopathic arthritis–associated macrophage activation syndrome, NLRC4 macrophage activation syndrome, cytokine release syndrome and sepsis.

Cytokine storms versus cytokine release syndrome

The term "cytokine storm" is often loosely used interchangeably with cytokine release syndrome (CRS) but is more precisely a differentiable syndrome that may represent a severe episode of cytokine release syndrome or a component of another disease entity, such as macrophage activation syndrome. When occurring as a result of a therapy, CRS symptoms may be delayed until days or weeks after treatment. Immediate-onset (fulminant) CRS appears to be a cytokine storm.

Research

Nicotinamide (a form of vitamin B₃) is a potent inhibitor of proinflammatory cytokines.

Magnesium decreases inflammatory cytokine production by modulation of the immune system.

History

The first reference to the term cytokine storm in the published medical literature appears to be by James Ferrara in 1993 during a discussion of graft vs. host disease; a condition in which the role of excessive and self-perpetuating cytokine release had already been under discussion for many years. The term next appeared in a discussion of pancreatitis in 2002, and in 2003 it was first used in reference to a reaction to an infection.

It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 17 to 50 million people. In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Taiwan also indicated this as the probable reason for many deaths during the SARS epidemic in 2003. Human deaths from the bird flu H5N1 usually involve cytokine storms as well. Cytokine storm has also been implicated in hantavirus pulmonary syndrome.

In 2006, a study at Northwick Park Hospital in England resulted in all 6 of the volunteers given the drug theralizumab becoming critically ill, with multiple organ failure, high fever, and a systemic inflammatory response. Parexel, a company conducting trials for pharmaceutical companies, in one of its documents, wrote about the trial and said theralizumab could cause a cytokine storm—the dangerous reaction the men experienced.

Relationship to COVID-19

During the COVID-19 pandemic, some doctors attributed many deaths to cytokine storms. Severe symptoms of acute respiratory distress syndrome (ARDS) with high mortality in COVID-19 patients are caused by a cytokine storm. SARS-CoV-2 activates the innate immune system and results in a release of a large number of cytokines, including IL-6, which can increase vascular permeability and cause a migration of fluid and blood cells into the alveoli as well as the consequent symptoms such as dyspnea and respiratory failure. The higher mortality is being linked to the result of ARDS aggravation and the tissue damage that can result in organ-failure and/or death.

ARDS was shown to be the cause of mortality in 70% of COVID-19 deaths. In a cytokine plasma level analysis of those with severe Sars-CoV-2, the levels of many interleukins and cytokines are extremely elevated, showing evidence of a cytokine storm in those most harshly affected. Additionally, postmortem examination of patients with COVID-19 has shown large accumulation of inflammatory cells in lung tissues, including macrophages and T-helper cells.

Early recognition of this cytokine storm in COVID-19 patients is crucial to ensure the best outcome, allowing for treatment with a variety of biological agents that target the cytokines to reduce their levels.

Due to the increased levels of cytokines and interferons in those with severe Sars-CoV-2, both are being investigated as potential therapies for COVID-19. An animal study done on mice found that those producing early strong interferon responses to SARS-CoV, which also originated from bats, were more likely to live, while other cases were likely to experience a highly morbid overactive immune system. The high mortality rate of COVID-19 in older populations were linked to the impact of age on interferon responses.

Short-term use of dexamethasone, a synthetic corticosteroid, has been demonstrated to reduce the severity of inflammation and lung damage induced by the cytokine storm; it inhibits the severe cytokine storm, or the hyperinflammatory phase in patients with COVID-19.

Trials continue to identify causes of cytokine storms in COVID-19 cases. One possible cause is the delayed type I INF response, because it leads to accumulation of pathogenic monocytes. High viremia is also associated with exacerbated type I INF response and worse prognosis. Diabetes, hypertension, and cardiovascular disease are all risk factors of cytokine storms in COVID-19 patients.

Cytokine

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cytokine 

3D medical animation still showing secretion of cytokines

Cytokines are a broad and loose category of small proteins (~5–20 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research.

Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell. They act through cell surface receptors and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. They are different from hormones, which are also important cell signaling molecules. Hormones circulate in higher concentrations, and tend to be made by specific kinds of cells. Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction.

The word comes from Greek: cyto, from Greek "κύτος" kytos "cavity, cell" + kines, from Greek "κίνησις" kinēsis "movement".

Discovery

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication. The activity of interferon-gamma (the sole member of the interferon type II class) was described in 1965; this was the first identified lymphocyte-derived mediator. Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.

In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines". In 1974, pathologist Stanley Cohen, M.D. (not to be confused with the Nobel laureate) published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine. Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.

Difference from hormones

Classic hormones circulate in nanomolar (10^-9 M) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10^-12 M) concentrations that can increase up to 1,000 times during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α. In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas. The current terminology refers to cytokines as immunomodulating agents.

A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic rather than local. For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxis, chemokinesis and endocrine as a pyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.

Nomenclature

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete.

• The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally white blood cells (leukocytes). It is now used largely for designation of newer cytokine molecules and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.
• Lymphokines: produced by lymphocytes
• Monokines: produced exclusively by monocytes
• Interferons: involved in antiviral responses
• Colony stimulating factors: support the growth of cells in semisolid media
• Chemokines: mediate chemoattraction (chemotaxis) between cells.

Classification

Structural

Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:

• The four-α-helix bundle family (InterPro: IPR009079): member cytokines have three-dimensional structures with a bundle of four α-helices. This family, in turn, is divided into three sub-families:
  1. the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO). They can be grouped into long-chain and short-chain cytokines by topology. Some members share the common gamma chain as part of their receptor.
  2. the interferon (IFN) subfamily.
  3. the IL-10 subfamily.
• The IL-1 family, which primarily includes IL-1 and IL-18.
• The cysteine knot cytokines (IPR029034) include members of the transforming growth factor beta superfamily, including TGF-β1, TGF-β2 and TGF-β3.
  • The IL-17 family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.

Functional

A classification that proves more useful in clinical and experimental practice outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1 (TNFα, IFN-γ, etc.), and those that enhance antibody responses, type 2 (TGF-β, IL-4, IL-10, IL-13, etc.). A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders. Several inflammatory cytokines are induced by oxidative stress. The fact that cytokines themselves trigger the release of other cytokines  and also lead to increased oxidative stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a). Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury. There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway.

Receptors

In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.

A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.

• Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
• Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).
• Interferon (type 2) family, whose members are receptors for IFN β and γ.
• Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named.
• Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.
• Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.

Cellular effects

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.

It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L. Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread papular eruptions.

Roles in health and disease

Cytokines are often involved in several developmental processes during embryonic development. Cytokines are crucial for fighting off infections and in other immune responses. However, they can become dysregulated and pathological in inflammation, trauma, sepsis, and hemorrhagic stroke.

Adverse effects

Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression and Alzheimer's disease to cancer. Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity.

Over-secretion of cytokines can trigger a dangerous cytokine storm syndrome. Cytokine storms may have been the cause of severe adverse events during a clinical trial of TGN1412. Cytokine storms are also suspected to be the main cause of death in the 1918 "Spanish Flu" pandemic. Deaths were weighted more heavily towards people with healthy immune systems, because of their ability to produce stronger immune responses, with dramatic increases in cytokine levels. Another example of cytokine storm is seen in acute pancreatitis. Cytokines are integral and implicated in all angles of the cascade, resulting in the systemic inflammatory response syndrome and multi-organ failure associated with this intra-abdominal catastrophe. In the COVID-19 pandemic, some deaths from COVID-19 have been attributable to cytokine release storms. Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in COVID-19 infections.

Medical use as drugs

Some cytokines have been developed into protein therapeutics using recombinant DNA technology. Recombinant cytokines being used as drugs as of 2014 include:

• Bone morphogenetic protein (BMP), used to treat bone-related conditions
• Erythropoietin (EPO), used to treat anemia
• Granulocyte colony-stimulating factor (G-CSF), used to treat neutropenia in cancer patients
• Granulocyte macrophage colony-stimulating factor (GM-CSF), used to treat neutropenia and fungal infections in cancer patients
• Interferon alfa, used to treat hepatitis C and multiple sclerosis
• Interferon beta, used to treat multiple sclerosis
• Interleukin 2 (IL-2), used to treat cancer.
• Interleukin 11 (IL-11), used to treat thrombocytopenia in cancer patients.
• Interferon gamma is used to treat chronic granulomatous disease and osteopetrosis